Abstract
Mammalian target of rapamycin (mTOR) is a protein serine/threonine kinase that was initially identified as the cellular target of rapamycin. This kinase regulates cell growth, proliferation, motility and survival, as well as the gene transcription and protein synthesis that are activated in response to hormones, growth factors and nutrients. Results from preclinical studies have indicated that factors antagonizing the mTOR pathway exert an antitumor effect on lung cancer. Furthermore, primary clinical trials of mTOR inhibitors have demonstrated that the inhibitors may be effective against lung carcinoma. The present study explores the association between mTOR and lung carcinogenesis and describes the clinical trials of mTOR inhibitors.
Highlights
Mammalian target of rapamycin is a protein serine/threonine kinase that was initially identified as the cellular target of rapamycin
Active mTORC1 exerts numerous downstream biological effects, including the translation of mRNA by phosphorylating downstream targets, such as 4E‐BP1 and p70 S6 kinase, the suppression of autophagy through Atg13 and ULK1, ribosome biogenesis, and activation of transcription that leads to increased mitochondrial activity or adipogenesis [21,22,23]. mTORC2, which consists of Mammalian target of rapamycin (mTOR), Rictor, GβL, Sin1, PRR5/Protor‐1 and DEPTOR, promotes cell survival through the activation of Akt [24,25]. mTORC2 regulates cytoskeletal dynamics, and ion transport and growth by activating PKCα and phosphorylating SGK1, respectively [26,27,28]. mTOR is a downstream target of EGFR and MET signaling, and is considered to be a therapeutically attractive target for the treatment of various types of cancer
All of the aforementioned preclinical and clinical trials revealed significant positive results for the use of mTOR antagonists in lung cancer. mTOR expression may be upregulated by numerous mechanisms in the pathogenesis of lung cancer
Summary
Numerous preclinical studies have suggested that mTOR and associated kinases are significant in the development of lung cancer. A two‐part phase I study assessed the antitumor activity, toxicity and pharmacokinetics of everolimus, administered weekly in 5‐30 mg doses, at increased weekly doses of 50‐70 mg and daily administration. Based therapy in combination with an EGFR antagonist These patients were administered everolimus at a dose of 10 mg daily. The observed toxicities were stomatitis, cough and dyspnea [48] Another phase II study investigated patients with SCLC. An additional phase I study assessed treatment with gefitinib and everolimus in patients with progressive NSCLC. The toxicities identified were diarrhea, mucositis and rash In another phase I trial, the combination of everolimus with erlotinib was investigated. This cohort consisted of patients with advanced NSCLC who had previously received two chemotherapy regimens and had an ECOG PS
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