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DOI: 10.1055/a-2507-3598
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Small Molecules in Medicinal Chemistry

Advancements in mTOR Inhibitors for Non-Small-Cell Lung Cancer: Mechanisms, Efficacy, and Future Perspectives

Aanal Thaker‡
a   Institute of Pharmacy, Nirma University, Ahmedabad 382481, India
,
Shrusti Patel‡
a   Institute of Pharmacy, Nirma University, Ahmedabad 382481, India
,
Rajdeep Dey
b   Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382481, India
,
Suman Shaw
b   Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382481, India
,
Hardik Bhatt
b   Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382481, India
,
Bhumika Patel
b   Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382481, India
,
Udit Chaube  ∗
b   Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382481, India
› Author Affiliations

This work was supported by the Minor Research Project (UID: IPNU/2024-26/144) funded by Nirma University, Ahmedabad, India.
› Further Information
 
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Abstract

This account comprehensively reviews the recent advancements in the development of mechanistic target of rapamycin (mTOR) inhibitors targeting non-small-cell lung cancer (NSCLC), focusing on their mechanisms, efficacy, and clinical trial statuses. Key small molecules such as RM-018 and RMC-4998 highlight novel approaches in targeting the KRASG12C mutation, offering enhanced potency compared to earlier inhibitors. Traditional and plant-derived compounds, including Fuzi alkaloids, salvianolic acid, and ononin, demonstrate promising antitumor activities through diverse pathways, such as the PI3K/AKT/mTOR signaling axis. Combination therapies targeting dual pathways show synergistic effects, improving treatment efficacy. The role of personalized medicine, driven by genetic profiling and pathway-specific inhibitors, is emphasized as a transformative approach in NSCLC management. These findings highlight the potential of mTOR-targeting agents as a cornerstone in advancing NSCLC therapies.

1 Introduction

2 Small-Molecule mTOR Inhibitors

3 mTOR Inhibitors in Clinical Trials

4 Conclusion and Future Directions


#

Key words

mTOR - small molecules - rapalogs - clinical trials - cancer

Biographical Sketches

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(from left to right) Aanal Thaker is currently pursuing a Bachelor of Pharmacy degree at Nirma University, Ahmedabad, Gujarat, India. Her research project, conducted under the guidance of Dr. Udit Chaube, involved the evaluation of thymol from Thymus linearis and its potential therapeutic application on rheumatoid arthritis. She is actively engaged in research with a focus on innovative therapeutic solutions. Her academic journey reflects a keen interest in the field of pharmaceutical sciences.


Shrusti Patel is currently pursuing a Bachelor of Pharmacy degree at Nirma University, Ahmedabad, Gujarat, India. Her academic work to date reflects a commitment to the field of pharmaceutical chemistry. Her research project was successfully carried out under the guidance of Dr. Udit Chaube, which involved an assessment of thymol obtained from Thymus linearis and its therapeutic implications for rheumatoid arthritis.


Rajdeep Dey obtained his B.Pharm. degree in 2016 (from GNIPST, West Bengal), his M.Pharm. degree in 2019 (from BIT Mesra Ranchi), and a PG Diploma in Regulatory Affairs (from GIRA, Pune). Rajdeep is a Ph.D. student at the Institute of Pharmacy, Nirma University, India, under the guidance of Dr. Hardik Bhatt, and performs research in structural biology, cancer research, molecular pharmacology, and medicinal chemistry. His area of research includes the design and synthesis of small molecules and their evaluation as potent therapeutic agents in cancer, HIV, tuberculosis, etc., and the development of green analytical chemistry methods for active pharmaceutical ingredients (APIs). In addition, he gained industrial experience as an analytical scientist at Strides Pharma Science Pvt. Ltd., Puducherry.


Suman Shaw received her M.Pharm. from BIT, Mesra, Ranchi and is currently a Ph.D. student at the Institute of Pharmacy, Nirma University, India, under the guidance of Dr. Hardik Bhatt. She undertakes research in computer-aided drug discovery, molecular biology, and organic synthesis in the areas of cancer and dengue. She is currently working on PI3K/mTOR inhibitors for cancer therapy. Suman is a student member of the American Chemical Society.


Hardik Bhatt is as an associate professor and Head of the Department of Pharmaceutical Chemistry, and has more than 20 years of teaching and research experience. His research interests include drug design with computational techniques, the synthesis of new chemical entities (NCEs) and their evaluation as potent therapeutic agents in the areas of cancer, HIV, tuberculosis, and the development of green analytical chemistry methods for active pharmaceutical ingredients (APIs). He has published over 57 research and review articles in reputed journals and has more than 110 presentations to his credit. He has reviewed international research grants as well as many articles. He has been actively involved in organizing national and international conferences/workshops in various capacities. Dr. Bhatt is a member of the Royal Society of Chemistry (MRSC), the American Chemical Society, the Indian Pharmaceutical Association, the Indian Society for Chemists and Biologists, the Association for Pharmacy Teachers of India, and the Indian Society for Technical Education.


Bhumika Patel received a Ph.D. in pharmaceutical science from the Institute of Pharmacy, Nirma University, India and is currently as an assistant professor in the Department of Pharmaceutical Chemistry. She has around 16.5 years of teaching experience. Her area of research includes the rational design and synthesis of different heterocyclic compounds for various therapeutic classes, such as diabetes, cancer, HIV, and so forth. She has 28 international publications in reputed journals and has given 29 presentations to her credit. Currently, she is working as co-principal investigator on a major research project on the design and synthesis of telomerase inhibitors for the treatment of cancer, funded by Nirma University. She is a life member of several professional bodies including the Association for Pharmacy Teachers of India (APTI), the Indian Pharmaceutical Association (IPA), the Indian Society of Chemists and Biologists (ISCB), the Research Society for the Study of Diabetes in India (RSSDI) and the Indian Society for Technical Education (ISTE).


Udit Chaube serves as an assistant professor in the Department of Pharmaceutical Chemistry at the Institute of Pharmacy, Nirma University, Ahmedabad. With a decade of experience in research and teaching, he completed his Ph.D. as a full-time scholar, supported by a DST-INSPIRE Fellowship from the Department of Science & Technology, Government of India. He is also a gold medalist, having secured the top position in his M.Pharm. program. Dr. Chaube has authored 17 research articles in reputed international journals. Before joining Nirma University, he was associated with the National Innovation Foundation-India, an autonomous body under the Department of Science & Technology, Government of India. He has presented over 14 research papers at various national and international conferences and seminars, demonstrating his active engagement in the academic community. His areas of expertise include synthetic chemistry, computational chemistry, cell culture, and in vivo biological evaluation. In recognition of his contributions, he is also a member of the editorial board of Nature Scientific Reports, a distinguished international journal.

1

Introduction

Cancer is characterized by abnormal cell growth that can invade or spread to other body parts, and has become a crucial public health challenge.[1] The most effective approach for consistently lowering global cancer mortality rates includes broad access to personalized treatments and increased funding for cancer drug development.[2] Cancer can originate in almost any part of the human body, composed of trillions of cells. It is fundamentally a genetic disease caused by alterations in the genes that regulate cellular functions. When cancer spreads from its original site to other parts of the body, it is referred to as metastatic cancer. This process of cancer cells spreading to distant areas of the body is known as metastasis. While treatment for metastatic cancer can sometimes prolong a patient’s life, in many cases, the primary goal is to manage and control the progression of the disease. Cancer encompasses a wide range of types, each categorized by the origin of the tumor and the specific cells affected. For instance, carcinomas arise from epithelial cells, while sarcomas originate in connective tissues. Other types include leukemia, which affect blood-forming tissues; lymphomas and myelomas, which involve the lymphatic and immune systems; and melanomas, which develop from pigment-producing cells. Additionally, there are gliomas, meningiomas, and medulloblastomas, which are cancers of the brain and spinal cord.[3] [4] Other examples include ovarian and testicular germ cell tumors, extragonadal germ cell tumors, as well as cancers of the lung, bladder, breast, colon, kidney, and pancreas, among others.[5]

In 2022, there were an estimated 20 million new cancer cases and 9.7 million deaths. The estimated number of people who were still alive within 5 years following a cancer diagnosis was 53.5 million. About 1 in 5 people develop cancer in their lifetime, approximately 1 in 9 men and 1 in 12 women die from the disease. Lung cancer was the most commonly occurring cancer worldwide with 2.5 million new cases accounting for 12.4% of the total new cases. Female breast cancer ranked second (2.3 million cases, 11.6%), followed by colorectal cancer (1.9 million cases, 9.6%), prostate cancer (1.5 million cases, 7.3%), and stomach cancer (970,000 cases, 4.9%). According to the National Institutes of Health (NIH), the estimated new cases of lung cancer in 2024 were 234,580, 11.7%, and the estimated number of deaths in 2024 was 125,070 (20.4%). Approximately 5.7% of men and women will be diagnosed with lung cancer at some point during their lifetime, based on 2018–2021 data, excluding 2020 due to COVID-19.

The mechanistic target of rapamycin (mTOR) is a central regulator of cell growth, proliferation, and survival, making it a critical therapeutic target in non-small-cell lung cancer (NSCLC).[6] Dysregulation of mTOR signaling often occurs due to mutations in upstream pathways such as PI3K/AKT or loss of PTEN, promoting tumor progression and treatment resistance.[7] [8] Targeting mTOR with selective inhibitors, including rapalogs and dual mTORC1/2 inhibitors, has shown significant promise in preclinical and clinical studies by suppressing tumor growth, reducing angiogenesis, and enhancing the efficacy of chemotherapeutic agents. Combining mTOR inhibitors with targeted therapies, such as EGFR inhibitors or immunotherapy, has the potential to overcome resistance mechanisms and improve patient outcomes in NSCLC.[9] This makes mTOR an attractive and viable target for therapeutic intervention in lung cancer management.[10,11] Lung cancer is divided into two main types: non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC).[12] Because NSCLC is so common and includes a wide variety of molecular pathways, research has concentrated on pinpointing certain signaling pathways that promote tumor growth and might provide targets for treatment. Particularly in NSCLC, the mammalian target of the rapamycin (mTOR) pathway has become a viable target for intervention among these pathways.[13] Cell development, proliferation, and survival are regulated by the mTOR signaling system, and lung cancer is one of the malignancies linked to its dysfunction.[14] Targeting mTOR in the therapy of lung cancer is especially attractive because it helps regulate oncogenic processes, such as protein synthesis and cell metabolism, which are frequently hyperactive in cancer cells. In lung cancer models, blocking mTOR may reduce tumor growth and increase survival, according to several studies, which makes it a desirable target for the development of new treatments.[15] In this account article, we have focused on small-molecule inhibitors and their clinical trial statuses for the treatment of lung cancer.[16]

Specifically, this account highlights several small-molecule inhibitors with distinct mechanisms of action compared to existing treatments for lung cancer. For example, sotorasib (1), adagrasib (2), RM-018 (3), and RMC-4998 (4) exhibit unique mechanisms, while RMC-6272 (5) has demonstrated significant activity against mTORC1. Another notable inhibitor, doxazosin (6), targets vasculogenic mimicry. Additionally, the activation of the ELK1/mTOR/S6K1 pathway has contributed to the development of gefitinib (7) (see Figure [1]).

The traditional Chinese medicine Fuzi has been employed in treating malignancies, with Fuzi alkaloids demonstrating efficacy in inhibiting the growth of NSCLC. Similarly, salvianolic acid targets vasculogenic mimicry to inhibit tumor development. Plant-derived compounds such as ononin (8) and paclitaxel (PTX) (9) have also shown effective antitumor activity (see Figure [1]). Furthermore, NRF2 inhibition by ML385 has shown promise in reducing tumor development.

Several mTOR inhibitors, including temsirolimus (10), compound 11, sepanisertib (12) and torkinib (13) (see Figure [2]), are commonly used in clinical and preclinical stages, due to their efficacy in targeting key pathways involved in lung cancer progression.[17] Proteins such as RICTOR and RPTOR of the PI3K/mTOR pathway are inhibited either in combination with carboplatin-paclitaxel or as standalone treatments.[18] Deletion of MARK2/4 has also been shown to reduce aerobic glycolysis and cell growth in non-small-cell lung cancer cells.

This account also examines numerous other small-molecule inhibitors and provides a comprehensive discussion of their mechanisms, therapeutic potential, and clinical trial statuses, building on the examples mentioned above.


# 2

Small-Molecule mTOR Inhibitors

Nokin et al. reported the development of small-molecule mTOR inhibitors and investigated their effectiveness in treating non-small-cell lung cancer (NSCLC).[19] Their work highlighted KRASG12C inhibitors, including compounds 1 and 2, which target the inactive state of the KRAS protein. Additionally, they introduced a new class of active-state inhibitors: compounds 3 and 4. The sensitivity to both classes of agents was found to be strongly correlated with the inhibition of mTORC1 activity.[19] [20]

KRASG12C is a mutation in the KRAS gene that drives the uncontrollable growth of cancer cells. While existing medications like sotorasib (1) and adagrasib (2) are designed to inhibit this mutation, only 37–43% of patients benefit from these treatments, underscoring the need for further advancements.[21] Active-state inhibitors, such as RM-018 (3) and RMC-4998 (4), offer a novel mechanism of action. Unlike their predecessors, these compounds form a complex with the KRASG12C protein and cyclophilin A, enabling them to inhibit the KRAS protein in its active form. This approach significantly enhances their ability to suppress cancer progression.[22]

The effectiveness of compounds 3 and 4 was tested on KRASG12C cell lines. Compound 3 was highly effective, with much lower IC50 values than adagrasib (2), while compound 4 was even more potent, showing 10 times better results than compound 3. This shows that compound 4 is very effective in targeting KRASG12C-mutated cancer cells.[23]

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Figure 1 Structures of small-molecule anticancer compounds: sotorasib (1), adagrasib (2), RM-018 (3), RMC-4998 (4), RMC-6272 (5), doxazosin (6), gefitinib (7), ononin (8) and paclitaxel (9)

RMC-6272 (5) is another promising compound that selectively targets mTORC1 while sparing mTORC2 across a wide range of concentrations, distinguishing it from rapalink-1. Although currently a preclinical tool, its selective action on mTORC1 demonstrates significant potential for further development.[24]

Despite the inhibition of KRASG12C, some cancer cells continue to rely on the PI3K/mTOR pathway for survival and growth. To tackle this issue, Kitai et al. evaluated a combination of KRASG12C inhibitors with drugs targeting the mTORC1 segment of the PI3K/mTOR pathway. This combination therapy significantly reduced tumor size and effectively eliminated cancer cells, highlighting the critical role of dual-targeting strategies in treating NSCLC.[25]

Hsu et al. found that doxazosin (6) was highly effective in blocking vasculogenic mimicry (VM) in NSCLC.[26] VM is a process that helps cancer spread and resist treatment, leading to poor outcomes for patients, making it an important target for therapy. Using specific staining and imaging methods, these researchers found that compound 6 disrupted the formation of tube-like structures in A549 cancer cells and changed their shape. It also reduced the size and length of these tube structures with measurable effects at certain doses. Additionally, compound 6 blocked the breakdown of a protein, laminin-5γ2, which helps reshape the area around cells. It also lowered the levels of the proteins vimentin and fibronectin, which are linked to cancer spreading. These results showed that compound 6 effectively stops VM in NSCLC cells.[27] [28]

Zhao et al. identified ELK1 as a key regulator of the mTOR-S6K1 pathway.[29] They found that the overactivation of this pathway contributes to resistance to gefitinib (7) in NSCLC. Compound 7 is a drug used to treat NSCLC, but its effectiveness can be reduced due to resistance mechanisms. By silencing the mTOR gene in cells, these researchers observed a significant decrease in the IC50 values of compound 7. For instance, in cells where mTOR was silenced, the IC50 value using compound 7 dropped from 10.14 μmol/L to 2.61 μmol/L, indicating increased sensitivity to the drug. Similarly, in PC9G cells with mTOR knocked down, the IC50 value decreased from 21.88 μmol/L to 6.83 μmol/L. Further studies showed that S6K1, a kinase involved in cell growth and survival, plays a major role in resistance to EGFR-TKIs (epidermal growth factor receptor tyrosine kinase inhibitors) like compound 7. Elevated phosphorylation of S6K1, regulated by the mTOR pathway, is linked to this resistance. Inhibiting mTOR reduces S6K1 activity, which in turn restores sensitivity to compound 7 in resistant NSCLC cells. Additionally, resistant cells were found to have increased levels of the transcription factor ELK1, which drives the activation of the mTOR pathway and contributes to drug resistance. This highlights the importance of targeting the ELK1/mTOR/S6K1 pathway as a potential strategy to overcome resistance to compound 7 in NSCLC.[29]

Zhang et al. discovered that Fuzi (Aconiti Lateralis Radix Praeparata), a traditional Chinese medicine, shows significant potential for treating NSCLC. Fuzi alkaloids (FZA), including alkylolamine diterpenoid alkaloids, monoester diterpenoid alkaloids, and diterpenoid alkaloids, were found to effectively inhibit the growth of NSCLC cells in both laboratory experiments and animal studies.[30]

A network pharmacology study revealed that FZA works primarily through the PI3K/AKT-mTOR signaling pathway, other cancer-related pathways, and central carbon metabolism to exert its anticancer effects.[30] FZA demonstrated strong tumor-killing activity across five NSCLC cell lines, with IC50 values ranging from 22.41 to 139.57 μg/mL. This is significant because elevated activity in the PI3K/AKT-mTOR pathway is commonly observed in patients with NSCLC, making it a key target for treatment. Research showed that FZA inhibits NSCLC progression by regulating glycolysis via the PI3K/AKT-mTOR-signaling pathway. These findings suggest that Fuzi alkaloids, which modulate this critical pathway, could be a promising therapeutic option for treating NSCLC.[31] [32]

Ji et al. studied lung squamous cell carcinoma (LUSC) and found that its proliferation heavily depends on NRF2, especially in tumors with high NRF2 activity.[33] NRF2 is a key regulator of antioxidant responses and plays a critical role in the survival of many cancer types. Research using MGH7 LUSC cells showed that in laboratory experiments and animal studies, inhibiting NRF2, either genetically or with a small-molecule inhibitor (ML385), significantly reduced tumor growth and cell proliferation. This suggests that NRF2 is a promising therapeutic target, particularly in LUSC cases with high NRF2 activity. Around 25% of LUSC patients exhibit activated NRF2, which supports cancer cell survival by regulating metabolic demands, cell cycle progression, and oxidative stress. NRF2 also enhances mTORC1 signaling by promoting the phosphorylation of proteins like AKT and RagD, linking it to the PI3K-mTOR pathway. Inhibition of NRF2 using ML385 has shown promising results in slowing tumor progression, making it a potential treatment strategy for LUSC.[33] [34]

Gong et al. discovered that ononin (formononetin-7-O-β-d-glucoside) (8), a plant-derived compound from Astragali Radix, shows promising anticancer effects. It also helps protect against doxorubicin-induced cardiotoxicity by reducing endoplasmic reticulum (ER) stress and apoptosis, potentially activating the SIRT3/mTOR pathway.[35]

Paclitaxel (PTX) (9), a potent chemotherapy drug used to treat various types of cancer, was found to be minimally toxic to HCC827 and A549 cells at a concentration of 1 μM. However, when compound 8 was used at a concentration of 3 μM, it induced cell death in both A549 and HCC827 cells. In combination, compound 8 and PTX reduced colony formation in vitro compared to PTX alone. Additionally, this study showed that compound 8 enhances the apoptotic effect of PTX by increasing the generation of reactive oxygen species (ROS), which promotes cancer cell death. Importantly, compound 8 did not cause significant toxicity, suggesting its potential as a promising candidate for further development in the treatment of NSCLC.[36]

According to Yu et al., mTOR inhibitors are categorized into two types: ATP-competitive inhibitors and allosteric inhibitors, which target either mTORC1 or both mTORC1 and mTORC2.[37] Rapalogs, such as temsirolimus (10) (Figure [2]) are allosteric inhibitors that work by binding to FKBP12, disrupting mTORC1, and preventing cancer cell growth without causing cell death. Compound 10 is used to treat renal cell carcinoma, breast cancer, and neuroendocrine tumors. Ongoing research also shows evidence of dual inhibition of mTORC1/C2, e.g., by compound 11, as reported by Chaube et al., which displays an IC50 value of 3.42 μM.[38]

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Figure 2 Structures of compounds associated with mTOR activities: temsirolimus (10), compound 11 (reported by Chaube et al.),[38] sapanisertib (12), torkinib (13), carboplatin (14), salvianolic acid A (15), vitexin (16), compound 17 (reported by Lin et al.),[45] compound 18 (reported by Dey et al.),[63] pimasertib (19), SAR245409 (20) and everolimus (21)

ATP-competitive inhibitors, such as MLN0128 (sapanisertib) (12), target both mTORC1 and mTORC2, which helps overcome resistance, but they can cause more toxicity. Another ATP-competitive inhibitor, PP242 (torkinib) (13), is commonly used in cancer research and has shown anticancer activity in solid tumors and leukemia. Researchers are also exploring combination therapies and personalized approaches based on patient genetic profiles to improve treatment effectiveness and reduce resistance.[39] [40]

Natarajan et al. discovered that non-small-cell lung cancer tissues have higher levels of MARK2 (microtubule affinity-regulated kinase 2) and MARK4 (microtubule affinity-regulated kinase 4) compared to normal tissues, based on data from The Cancer Genome Atlas. MARK2 was found to help cancer cells grow and survive by promoting a process called aerobic glycolysis and blocking cell death through certain pathways. MARK4 also supported cancer cell growth and spread by interfering with the Hippo signaling pathway.

In NSCLC, higher levels of MARK2 and MARK4 were linked to more advanced cancer and worse survival rates. Experiments showed that blocking or removing MARK2/4 reduced cell growth and the process of aerobic glycolysis in NSCLC cells. This effect was further reduced by treatments like the AMPK activator AICAR, the mTOR inhibitor rapamycin, and a specific MARK2/4 inhibitor called 39621.

These findings suggest that MARK2/4 plays a role in cancer progression by changing the metabolism of cells in NSCLC. The research also showed that higher glucose levels increase MARK2/4 activity, which suppresses a protein (AMPK) and boosts a pathway (mTOR/HIF-1α) that support cancer growth. This points to the potential of targeting MARK2/4 as a treatment for lung cancer.[41]

Hung et al. found that some small-cell lung cancers (SCLC), especially those with PIK3CA mutations or PTEN loss, have constant activation of the PI3K pathway.[42] These tumors are more sensitive to specific inhibitors of PI3K, AKT, and mTOR, and can trigger cell death by cleaving proteins of the mTOR complex (RICTOR and RPTOR) through CASP6/3. In clinical studies, dual PI3K/mTOR inhibitors, either alone or combined with carboplatin (14) and compound 9, show promise in treating SCLC.[42] [43]

According to Jin et al., salvianolic acid A (15) (Sal-A), the key bioactive component of Salvia miltiorrhiza, has shown promise in preventing the progression of NSCLC.[44] Vasculogenic mimicry, a process that allows tumor cells to form blood vessels and spread more easily, has been linked to poor prognosis and increased invasiveness in NSCLC. Sal-A helps block vasculogenic mimicry, promotes apoptosis (cell death), and reduces invasiveness, potentially limiting the progression of the disease. These effects are mainly mediated through the PI3K/AKT/mTOR-signaling pathway. Sal-A also affects proteins like MMP2, N-cadherin, and E-cadherin, which are important for tumor cell invasion. By targeting key components of the PI3K/AKT/mTOR pathway, Sal-A selectively inhibits tumor growth and metastasis. However, the exact molecular pathways through which Sal-A affects vasculogenic mimicry, especially when combined with other drugs like AKT activators, are still not fully understood.[44]

Lin et al. found that due to the severe side effects associated with conventional chemotherapeutic drugs, improving drug selectivity is essential.[45] Several new fluorescent thiazole–pyrazoline compounds were produced in large quantities and were found to significantly inhibit the growth of A549 cells, outperforming 5-FU. An examination of the structure–activity relationship (SAR) revealed that the aryl group of the pyrazoline moiety at position 5 significantly increased activity, particularly by stopping the cell cycle at the G1 phase without inducing necrosis. A crucial feature of the function of compound 17 (Figure [2]) in autophagy is its selective lysosomal accumulation. Cellular processes such as autophagy maintain quality control over proteins and organelles. By specifically targeting FKBP12, a regulatory protein involved in mTOR signaling, compound 17 mechanistically blocked the PI3K/Akt/mTOR pathway. The phosphorylation of important proteins downstream of mTOR, RPS6KB1 and EIF4EBP1, was reduced, and this was reversible when 3BDO, a mTOR activator and autophagy inhibitor, was administered. FKBP12 knockdown also eliminated the inhibitory effects of compound 17, supporting its function as a target for mTOR regulation. Moreover, the effectiveness of compound 17 in vivo was assessed using the chorioallantois membrane model. It did not negatively impact angiogenesis or normal cell function, but it did dramatically decrease tumor development when compared to 5-FU. Further evidence that compound 17 increases autophagy in vivo and inhibits tumor development was provided by immunofluorescence experiments. The IC50 value of 17 is 2.6 ± 0.11 μM. The authors also demonstrated that compound 17 inhibited mTOR, though targeting FKBP12.[45]

It was discovered by Lee et al. that there was a correlation between the expression of CD109 and the invasive and metastatic potential of lung cancer cells.[46] Cluster of differentiation 109 (CD109) is a glycosyl-phosphatidyl-inositol (GPI)-anchored protein that belongs to the α2-macroglobulin/C3, C4, and C5 family. CD109 was found to be expressed by endothelial, platelet, and hematopoietic progenitor cells. In tumorous tissues, CD109 is increased. In patients with lung adenocarcinoma, CD109 overexpression has been linked to tumor development, distant metastasis, and a poor prognosis. The regulation of protein kinase-B (AKT)/mammalian target of rapamycin (mTOR) signaling is achieved through the mechanistic interaction of CD109 expression with the epidermal growth factor receptor (EGFR). CD109 inhibition reduces EGFR phosphorylation, lessens the activation of AKT/mTOR induced by EGF, and increases the susceptibility of tumor cells to EGFR inhibitors. The proliferation and invasiveness of lung adenocarcinoma cells are stimulated by CD109. The mTOR/AKT/protein kinase B (AKT) axis was one of the downstream signaling pathways regulated by CD109 expression, which was linked to EGFR. Additionally, CD109 contributes to EGFR-tyrosine kinase inhibitor (TKI) sensitivity, and CD109 overexpression has been linked to poor survival outcomes in patients with lung adenocarcinoma. The authors evaluated CD109 expression in a panel of lung cancer cell lines to better understand the role of CD109 in lung carcinogenesis. The results indicated that A549, H460, and PC9 cells had high levels of CD109 expression. It is interesting to note that the ability of lung cancer cells to migrate was strongly correlated with CD109 expression.[45] Following CD109 knockdown, the AKT signaling cascade, which includes mTOR, 70S6K, and GSK3β, was downregulated. Western blotting consistently showed that in A549, H460, and CL1-5 cells, CD109 knockdown reduced phosphorylation of AKT, mTOR, and 70S6K. On the other hand, mTOR and AKT phosphorylation was elevated by CD109 overexpression. In CD109-knockdown lung cancer cells, GSK3β, an AKT substrate, and its downstream target, cyclin D1, were also downregulated.[47] [48] [49] [50] Interestingly, the authors looked at the CD109 expression level in a panel of lung cancer cell lines in the Cancer Cell Line Encyclopedia (CCLE) database, and there was no discernible upregulation of CD109 between cell lines of squamous cell carcinoma and adenocarcinoma origin. CD109 was found to be upregulated in squamous cell carcinoma tissues. In this investigation, the authors discovered that elevated levels of CD109 expression were linked to a negative prognostic score for adenocarcinomas but not for squamous cell carcinoma. This suggests that CD109 expression is more crucial for the carcinogenesis of adenocarcinomas. Our results supported earlier research showing that among patients with lung cancer, CD109 is the best predictor of metastasis and survival. It is interesting to note that tobacco use is frequently mentioned as a significant risk factor for lung squamous cell carcinoma.[47,] [51–54]

Crees et al. identified three factors as potential prognostic markers for patients with lung cancer: EGFR/c-Met activation/amplification and co-expression, mTOR upregulation/activation, and Akt/Wnt signaling upregulation.[55] Each of these factors has been independently associated with a more aggressive disease course. The MET gene encodes c-Met, also known as the hepatocyte growth factor receptor (HGFR), a membrane-bound receptor tyrosine kinase (RTK). When amplified or activated, c-Met plays a crucial role in angiogenesis, metastasis, and tumor growth. Furthermore, the activation of c-Met signaling has been linked to the overexpression of several downstream signaling pathways, such as the RAS/MAPK, PI3K/Akt, and Wnt pathways.[55] The co-localization of c-Met and EGFR in NSCLC has been shown to enhance cell proliferation, activate downstream signal transduction, and may indicate an aggressive tumor phenotype associated with a worse prognosis. Additionally, in vitro studies have suggested that mTOR activation and the overexpression of Akt/Wnt signaling pathways are linked to more severe disease characteristics in NSCLC patients.[56]

Liu et al. discovered that the potential anticancer properties of natural products, particularly those derived from plants, have attracted significant attention from researchers in recent years.[57] One such compound is vitexin (16), also known as apigenin-8-C-d-glucopyranoside, a naturally occurring flavonoid found in the traditional Chinese herb Crataegus pinnatifida. Vitexin has shown antitumor activity against various human cancers, including glioblastoma, hepatocellular carcinoma, and leukemia. The current study aimed to investigate the anti-NSCLC effects of vitexin, both in vitro and in vivo, and to explore the molecular pathways involved.[57] [58]

The researchers confirmed that xenograft tumors grew at the injection sites in all mice. Treatment with vitexin significantly inhibited the growth of these NSCLC tumors. Additionally, the average tumor weight was notably reduced after vitexin treatment. They also observed changes in the tumor tissues, with an increase in the expression of cleaved caspase-3 and Bax, alongside a decrease in Bcl-2 expression. The team further explored how vitexin affected the PI3K/Akt/mTOR signaling pathway in NSCLC cells.[59] Western blot analysis revealed that vitexin administration dose-dependently decreased the levels of p-PI3K, p-Akt, and p-mTOR in A549 cells.[60]

Vitexin (16) may also have broader anticancer properties against other malignancies, such as esophageal cancer, where it can induce apoptosis and inhibit cell proliferation. In the present study, vitexin decreased A549 cell survival in vitro and increased LDH release due to cell membrane disruption. Moreover, vitexin treatment also inhibited the growth of NSCLC tumors in vivo, confirming its anti-NSCLC potential. A key approach in cancer treatment is to stimulate apoptotic pathways, a form of cell death conserved throughout evolution.[61]

The release of pro-apoptotic factors is triggered by the loss of mitochondrial membrane potential (MMP), a crucial organelle involved in cell death. The study showed that vitexin reduced the Bcl-2/Bax ratio and released cytochrome c into the cytoplasm, leading to the activation of caspase-3, a critical executor of caspase in A549 cells. Based on these findings, the researchers hypothesized that vitexin induces apoptosis in A549 cells through a mitochondria-dependent mechanism. This study may be the first to demonstrate that both the mitochondrial pathway and PI3K/Akt/mTOR signaling contribute to the damage and death of A549 cells induced by vitexin treatment, as both in vitro and in vivo studies were conducted. Compound 16 appears to be a promising and effective potential treatment for NSCLC, although further research is required to confirm these results.[62]

In this study, Wang et al. found that resveratrol exerted an antitumor effect by inhibiting cell proliferation and promoting cell apoptosis in NSCLC cells dose-dependently.[63] Resveratrol (trans-3,4′,5-trihydroxystilbene) is a natural polyphenolic phytoalexin, which is found in the skins of red grapes, red wine, and peanuts. Their findings indicated that resveratrol activated SIRT1 to induce protective autophagy in NSCLC cells via inhibiting Akt/mTOR and activating the p38-MAPK pathway. Therefore, inhibition of protective autophagy may enhance the antitumor activity of resveratrol in NSCLC. A Western blot analysis was performed to detect the activated state of associated proteins in A549 cells that were treated with different concentrations of resveratrol. The results showed that resveratrol inhibited the phosphorylation of Akt, mTOR, and p-70S6K while increasing the phosphorylation of p-38, thus resulting in decreased ratios of p-Akt/Akt, p-mTOR/mTOR, and p-p-70S6K/p-70S6K, and an increased ratio of p-p-38/p-38 in a dose-dependent manner.[63]

Dey et al. reported several tetrahydroquinoline analogues as apoptosis inducers and mTOR inhibitors for treating lung cancer. All the synthesized compounds were screened against breast cancer, colon cancer, and lung cancer cell lines. Among all the synthesized tetrahydroquinoline analogues, compound 18 was reported to be the most active, exhibiting an IC50 value of 0.082 μM in lung cancer cell lines (A549).[64]


# 3

mTOR Inhibitors in Clinical Trials[16]

The structures of the drugs and mTOR inhibitors described in this section can be found in Figures [1–5]. Additionally, the clinical trial status of mTOR inhibitors, along with their respective sponsors, is presented in Table 1.

Nab-rapamycin/ABI-009 (18): A Phase I/II study is investigating the safety, toxicity, and potential antitumor effects of sequentially administering nivolumab, followed by increasing doses of the mTOR inhibitor. The study focuses on advanced cases of various cancers, including Ewing’s sarcoma, PEComa, epithelioid sarcoma, desmoid tumors, chordoma, non-small-cell lung cancer, small-cell lung cancer, urothelial carcinoma, melanoma, renal cell carcinoma, squamous cell carcinoma of the head and neck, hepatocellular carcinoma, classical Hodgkin’s lymphoma, MSI-H/dMMR metastatic colorectal cancer, and tumors with genetic mutations that may respond to mTOR inhibitors.[36]

Pimasertib/MSC1936369B (MEK inhibitor) (19) and SAR245409 (20) (PI3K and mTOR inhibitors): This Phase I study is testing two experimental compounds, 19 and 20 (Figure [2]), for treating solid tumors that have spread or metastasized. The primary goal of the study is to determine the maximum tolerable dose of the combination of these drugs.[21]

Everolimus (21): This Phase 1b randomized, pre-operative lung cancer study evaluates the metabolic response to RAD001 treatment in patients with operable lung cancer. The response is assessed using PET scans, measuring a 50% reduction in the standardized uptake value (SUV) from baseline to pre-surgery. Additionally, the study examines the safety of RAD001 and its impact on overall and progression-free survival following surgery and adjuvant chemotherapy (cisplatin and docetaxel). A Phase 2 study explores the efficacy and safety of everolimus (21) (Figure [2]) in patients with advanced NSCLC. The investigation is based on the need for better treatment options for advanced NSCLC, given the limited effectiveness of current therapies, and the association of cell-signaling pathways targeted by everolimus with oncogenesis, disease progression, and treatment resistance.[61] Evidence from preclinical models showed the effectiveness of everolimus and rapamycin in lung cancer.[65] [66]

Enhanced PI3K/Akt/mTOR signaling, which everolimus inhibits, may play a key role in cancer development, progression, and treatment resistance.[67] The use of everolimus in advanced NSCLC represents a novel approach, targeting the regulatory pathways of cells to control tumor growth, viz., a Phase 1 trial investigated the combination of everolimus and BKM120 in patients whose cancer no longer responded to conventional treatments or who could not tolerate standard therapy. The study aimed to assess the safety, side effects, and optimal dosages of these drugs when used together. Another goal was to evaluate the effectiveness of the combination by analyzing patient responses.[68] [69] [70]

Monoclonal antibodies, such as cixutumumab, prevent tumor growth by blocking tumor cell proliferation, targeting and destroying tumor cells, or delivering toxic compounds to tumors. Everolimus inhibited enzymes needed for cell division, while octreotide acetate (37) slowed neuroendocrine carcinoma growth by disrupting tumor cell proliferation. This Phase 1 trial studied the side effects and optimal doses of cixutumumab, everolimus, and octreotide acetate (37) in patients with advanced low- or intermediate-grade neuroendocrine cancer.[71]

Another Phase 1 trial investigated the combination of everolimus and vatalanib in patients with advanced solid tumors. These drugs blocked enzymes required for tumor growth and reduced blood flow to tumors. Their combined use enhanced tumor-killing effects.[72] [73] [74]

A prospective multicenter, randomized Phase 2 study evaluated the safety and effectiveness of everolimus and pasireotide LAR, both individually and in combination, for treating advanced neuroendocrine carcinoma of the lung and thymus. Approximately 108 patients were enrolled, with 36 patients assigned to each treatment group. Patients with stable disease (SD) or who were better after 12 months of treatment were allowed to continue therapy if tolerated. The primary endpoint was the percentage of patients without disease progression at 12 months, assessed using RECIST v1.1.[75]

Another Phase 2 trial compared lutetium Lu 177 dotatate to everolimus in treating patients with advanced somatostatin receptor-positive bronchial neuroendocrine tumors. Lutetium Lu 177 dotatate delivers radiation directly to tumor cells, potentially reducing damage to normal cells and outperforming everolimus in shrinking or stabilizing tumors.[76] [77]

A Phase 1/2 trial evaluated the optimal dosing, side effects, and effectiveness of combining compounds 7 and 21 in patients with stage IIIB, stage IV, or recurrent NSCLC. These drugs may inhibit enzymes essential for tumor growth, and their combination may enhance tumor cell death.[78] [79] [80]

Table 1 Small-Molecule mTOR Inhibitors in Clinical Triala

Drug

NCT Number

Study Status

Conditions

Sponsor

Phase(s)

nab-rapamycin (18)

NCT03190174

completed

NSCLC

Sarcoma Oncology Research Center, LLC

Phase I/II

pimasertib (19), SAR245409 (20) (PI3K and mTOR inhibitor)

NCT01390818

completed

NSCLC

EMD Serono

Phase I

everolimus (21)

NCT00401778

completed

lung cancer

Emory University

Phase I

AMG 954/panitumumab

NCT00352950

withdrawn

NSCLC

Amgen

Phase I

itraconazole (22)

NCT02357836

completed

NSCLC

University of Texas Southwestern Medical Center

early Phase I

BKM120 (23), everolimus (21)

NCT01470209

completed

lung cancer

Emory University

Phase I

everolimus (21)

NCT00124280

completed

NSCLC

Novartis Pharmaceuticals

Phase II

FDG-PE (24), pemetrexed (25), sirolimus (26), dexamethasone (27)

NCT00923273

terminated

carcinoma, NSCLC

National Cancer Institute (NCI)

Phase I/II

temsirolimus (10)

NCT00079235

completed

NSCLC

National Cancer Institute (NCI)

Phase II

SAR245409 (20), erlotinib (28)

NCT00777699

completed

NSCLC

Sanofi

Phase I

itraconazole (22)

NCT03664115

unknown

lung cancer

Ain Shams University

Phase II

sirolimus (26), gold sodium thiomalate (29)

NCT01383668

withdrawn

NSCLC, squamous cell lung cancer

Mayo Clinic

Phase I

metformin (30)

NCT02019979

terminated

NSCLC stage IIIB/IV

NSCLC metastatic

non-squamous non-small cell neoplasm of lung

Beth Israel Medical Center

Phase II

metformin (30) XR, delayed metformin (30), sirolimus (26)

NCT02145559

completed

lung neoplasms

University of Chicago

Phase I

palbociclib (31), gedatolisib (32)

NCT03065062

recruiting

lung cancer squamous cell, head and neck cancer, pancreatic cancer

Dana-Farber Cancer Institute

Phase I

gedatolisib (32), paclitaxel (9), carboplatin (14)

NCT02920450

terminated

NSCLC

University of Florida

Phase I/II

auranofin (33), sirolimus (26)

NCT01737502

completed

extensive stage NSCLC, lung adenocarcinoma, NSCLC, squamous cell lung carcinoma stage IIIA, NSCLC stage IIIB, NSCLC stage IV

Mayo Clinic

Phase I/II

durvalumab, sirolimus (26)

NCT04348292

terminated

NSCLC

Emory University

Phase I

CC-223 (34), erlotinib (28), CC-223 (34), oral azacitidine (35)

NCT01545947

completed

carcinoma, NSCLC

Celgene

Phase I

BAY 43-9006 (sorafenib) (36)

NCT00098254

completed

NSCLC

National Cancer Institute (NCI)

Phase II

everolimus (21), octreotide acetate (37)

NCT01204476

completed

lung carcinoid tumor

National Cancer Institute (NCI)

Phase I

chemotherapy before RAPA-201 therapy

NCT05144698

recruiting

NSCLC

Rapa Therapeutics LLC

Phase I/II

everolimus (21), vatalanib (38)

NCT00655655

completed

NSCLC

Mayo Clinic

Phase I

CC-223 (34)

NCT01177397

completed

NSCLC

Celgene

Phase I/II

metformin hydrochloride (30)

NCT05445791

recruiting

NSCLC

Instituto Nacional de Cancerologia de Mexico

Phase III

pasireotide (39) LAR, everolimus (21), pasireotide (39) LAR, everolimus (21), combination

NCT01563354

completed

neuroendocrine carcinoma of the lung and thymus

Novartis Pharmaceuticals

Phase II

everolimus (21)

NCT01563354

completed

lung neuroendocrine neoplasm

Novartis Pharmaceuticals

Phase I

AZD-2014 (40), AZD-6244 (41)

NCT02583542

unknown

squamous cell lung cancer, non-squamous cell lung, cancer with KRAS mutations, non-squamous cell lung cancer with wild-type KRAS

Queen Mary University of London

Phase I/II

everolimus (21)

NCT04665739

recruiting

advanced lung neuroendocrine tumor

National Cancer Institute (NCI)

Phase II

RAD001 (21), docetaxel (42)

NCT00406276

terminated

lung cancer

Emory University

Phase I/II

VS-6766 (43), everolimus (21)

NCT02407509

recruiting

lung cancer

Royal Marsden NHS Foundation Trust

Phase I

everolimus (21), gefitinib (7)

NCT00096486

completed

lung cancer

Memorial Sloan Kettering Cancer Center

Phase I/II

AZD4547 (44), vistusertib (40), palbociclib (31), Crizotinib (45), Selumetinib (41), docetaxel (42), AZD5363 (46), osimertinib (47), durvalumab, sitravatinib (48), AZD6738 (49)

NCT02664935

active not recruiting

NSCLC

University of Birmingham

Phase2

a All clinical trial data were retrieved from https://clinicaltrials.gov, on 10/24/2024. Onatasertib, ATG-008, and CC-223 are synonyms.

An open-label, single-arm Phase 1/2 trial evaluated the safety and effectiveness of RAD001 combined with docetaxel in patients with recurrent NSCLC. The results were compared with published Phase II and III data for docetaxel alone.[3] [81] [82]

For lung cancer, new drugs and treatment strategies are urgently needed. While some progress has been made with novel therapies, significant advancements require further research. Targeting the mTOR axis, which is known to be abnormal in NSCLC, and applying this knowledge to develop treatments, may lead to meaningful improvements in lung cancer management.[83]

AMG954/Panitumumab: This Phase 1 study determined the optimal dose and schedule of sirolimus (26) when administered in combination with panitumumab in adult subjects with stage IIIB/IV NSCLC.[84] [85]

Itraconazole (22): This clinical investigation was in its initial stages. The main focus was on pharmacodynamic endpoints, with clinical data, including safety, also being collected. The researchers aimed to determine how itraconazole (22) affected tumor angiogenesis, the Hh pathway, and how these effects were predicted by biomarkers. They also looked at how the pharmacokinetics of itraconazole were related to these effects and how various biomarkers were connected.[86] Additionally, itraconazole (22) directly disrupted ATP production in the mitochondria, activating the AMP-activated protein kinase pathway and inhibiting the mTOR pathway.[87]

Zoom Image
Figure 3 The structures of compounds 22–33 used as mTOR inhibitors in various phases of clinical trials

Temsirolimus (10): This Phase II trial is studying how well CCI-779 works in treating patients with stage IIIB non-small-cell lung cancer (with pleural effusion) or stage IV non-small-cell lung cancer. Drugs used in chemotherapy, such as CCI-779, work in different ways to stop tumor cells from dividing so they stop growing or die. CCI-779 may also stop the growth of tumor cells by blocking the enzymes necessary for their growth.[88]

Erlotinib (28): The purpose of this Phase 1 study was to evaluate the safety and tolerability of XL765 in combination with erlotinib (28) (Tarceva®) in subjects with solid tumors. XL765 is a new chemical entity that inhibits the kinases PI3K and mTOR. In preclinical studies, inhibiting PI3K was shown to block tumor growth and induce apoptosis, while inhibiting mTOR was shown to prevent tumor cell growth. Erlotinib (28) is an orally administered EGFR (HER1) tyrosine kinase inhibitor approved by the FDA for treating locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen and in combination with gemcitabine for first-line treatment of locally advanced, unresectable, or metastatic pancreatic cancer. The primary goal of this initial study was to determine the maximum tolerated dose level for each combination to assess their effects in future clinical trials for advanced NSCLC. This was part of a larger study combining the investigational dual mTOR inhibitor, CC-223 (34), with other agents, such as erlotinib (28) or oral azacytidine.[89] [90]

Zoom Image
Figure 4 The structures of compounds 34–41 used as mTOR inhibitors in various phases of clinical trials

Sirolimus (26): This Phase I trial studies the side effects and best dose of compound 26 and gold sodium thiomalate (29) when given together in treating patients with advanced squamous non-small cell lung cancer.[91] Compound 26 and gold sodium thiomalate (29) may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.[41]

The combination of metformin (30) plus compound 26 results in a reduction of p4EBP1, p70S6K and pAKT more than compound 26 alone in peripheral blood T-cells (PBTC).[6]

The combination of compounds 30 and 26 will result in decreased levels of serum biomarkers including fasting insulin, C-peptide, glucose, triglycerides, LDH, IGF-1, IGF-1R, IGF-BP and leptin, but an increase in adiponectin in peripheral blood. This Phase I/II trial examines the side effects and optimal dosage of auranofin (33) when combined with compound 26.[92] It also aims to determine how well auranofin (33) treats patients whose lung cancer has spread to other parts of their body, is incurable or uncontrollable with treatment, or has returned after a period during which the cancer was not detectable. Lung cancer development may be halted or slowed by compounds 33 and 26.[93] [94] [95]

Another trial studied the side effects of compound 26 and durvalumab to see how well they work in treating patients with stage I-IIIA non-small-cell lung cancer. Compound 26 is an oral medication that blocks the mTOR cellular pathway, which may help the immune system work better. Immunotherapy with monoclonal antibodies, such as durvalumab, may help the immune system of the body attack cancer and may interfere with the ability of tumor cells to grow and spread. Giving sirolimus (26) before durvalumab may help the immune system eliminate cancer.[96]

Metformin (30) is thought to activate AMP-activated protein kinase (AMPK),[97] a major sensor of cellular energy levels and a key enzyme limiting cellular growth during times of cellular stress. Once activated, this enzyme restricts anabolic processes such as protein, cholesterol and fatty acid synthesis and inhibits mTOR, a protein kinase responsible for unregulated growth. MTOR is upregulated in a variety of tumors, including NSCLC, providing rationale to take advantage of this pathway with metformin (30).[99]

Palbociclib (31): The safety of an experimental medicine or combination of investigational pharmaceuticals is tested in an open-label Phase I clinical trial, which also attempts to determine the right dosage of the investigational drug or drugs to employ in subsequent research. ‘Investigational’ indicates that the medication is under investigation. A combination of medications is being investigated in this study as a potential cancer therapy that may cause a particular alteration in the phosphatidylinositol-3 phosphate (PI3K) pathway.[99]

Several simultaneous multi-center single-arm Phase II trial arms make up the study, each of which tests an investigational targeted medication in a population stratified by many pre-specified actionable target putative biomarkers. The main goal is to assess the presence of an activity signal in each drug-(putative)biomarker cohort.[100]

Zoom Image
Figure 5 The structures of compounds 42–49 used as mTOR inhibitors in various phases of clinical trials

Gedatolisib (32), paclitaxel (9), and carboplatin (14): This study will consist of two Phases, Ib and II. The Phase Ib portion will study dose escalations in separate 3+3 cohorts using escalating doses of PF-05212384. The Phase II portion will consist of a two-stage Simon design. The doses for paclitaxel (9) (200 mg/m2, Q21 days) and carboplatin (AUC = 6, Q21 days) do not adjust as part of the study design. The dose of PF-05212384 will be determined during the Phase Ib portion.[101]

Sorafenib (36): The benefits and adverse effects of BAY 43-9006 (36) in patients with advanced, recurring, or refractory non-small cell lung cancer will be examined in this Phase 2 research. One of a novel class of anticancer drugs is called biaryl urea – BAY 43-9006 (36).[102] [103] Several clinical trials are evaluating targeted therapies for lung cancer. The AZD-2014 (40) and AZD-6244 (41) trial (NCT02583542) at Queen Mary University of London investigates their effects on various lung cancer subtypes but has an unknown status. Everolimus (21) (NCT04665739) is in Phase II at the NCI for advanced lung neuroendocrine tumors, while the Everolimus (21) and Docetaxel (42) trial (NCT00406276) was terminated. The VS-6766 (43) and Everolimus (21) study (NCT02407509) is ongoing at Royal Marsden. Additionally, AZD-4547 (44), Vistusertib (40), Palbociclib (31), and other agents like Selumetinib (41), Docetaxel (42), Crizotinib (45), AZD-5363 (46), Osimertinib (47), Sitravatinib (48), AZD6738 (49) are being tested in an active but non-recruiting NSCLC trial (NCT02664935) at the University of Birmingham.


# 4

Conclusion and Future Directions

This account underscores the pivotal role of mTOR signaling in non-small cell lung cancer (NSCLC) and highlights the development of small-molecule inhibitors with unique mechanisms of action. Compounds such as RM-018 and RMC-4998 target the KRASG12C mutation more effectively than earlier inhibitors, offering a promising approach for overcoming resistance. Plant-derived agents like Fuzi alkaloids and salvianolic acid show significant tumor inhibition by modulating pathways like PI3K/AKT/mTOR and vasculogenic mimicry. Dual-targeting strategies combining mTOR inhibitors with chemotherapeutic agents or other pathway-specific inhibitors, such as EGFR-TKIs, demonstrate synergistic effects, enhancing therapeutic outcomes. These findings collectively emphasize the therapeutic potential of mTOR inhibitors in the management of NSCLC and their ability to address challenges such as resistance and the limited efficacy of current treatments.

Future directions should focus on several critical areas to advance the application of mTOR inhibitors. First, efforts must be directed toward optimizing the pharmacokinetic and pharmacodynamic profiles of these compounds to enhance their bioavailability and minimize toxicity. The integration of mTOR inhibitors with immunotherapeutic agents, such as immune checkpoint inhibitors, could provide a dual benefit of direct tumor inhibition and immune system activation. Furthermore, leveraging advances in genetic profiling and artificial intelligence can help identify patient-specific biomarkers and design tailored combination therapies.

The exploration of delivery systems, such as nanoparticles and liposomes, holds promise for improving the precision and safety of mTOR-targeting agents. Combining these inhibitors with emerging technologies, such as CRISPR-Cas9, offers opportunities to target tumor-specific mutations more effectively, potentially reducing off-target effects. Expanding clinical trials to include diverse patient populations and conducting longitudinal studies will be crucial to validating the long-term efficacy and safety of these treatments. By addressing these future directions, the potential of mTOR inhibitors to revolutionize NSCLC treatment and significantly improve patient outcomes can be fully realized.


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in his account, apart from those disclosed. No writing assistance was utilized in the production of this manuscript.


Corresponding Author

Udit Chaube
Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University
Ahmedabad 382481
India   

Publication History

Received: 30 November 2024

Accepted after revision: 20 December 2024

Accepted Manuscript online:
20 December 2024

Article published online:
12 February 2025

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Zoom Image
Zoom Image
Figure 1 Structures of small-molecule anticancer compounds: sotorasib (1), adagrasib (2), RM-018 (3), RMC-4998 (4), RMC-6272 (5), doxazosin (6), gefitinib (7), ononin (8) and paclitaxel (9)
Zoom Image
Figure 2 Structures of compounds associated with mTOR activities: temsirolimus (10), compound 11 (reported by Chaube et al.),[38] sapanisertib (12), torkinib (13), carboplatin (14), salvianolic acid A (15), vitexin (16), compound 17 (reported by Lin et al.),[45] compound 18 (reported by Dey et al.),[63] pimasertib (19), SAR245409 (20) and everolimus (21)
Zoom Image
Figure 3 The structures of compounds 22–33 used as mTOR inhibitors in various phases of clinical trials
Zoom Image
Figure 4 The structures of compounds 34–41 used as mTOR inhibitors in various phases of clinical trials
Zoom Image
Figure 5 The structures of compounds 42–49 used as mTOR inhibitors in various phases of clinical trials