Abstract
BackgroundLung cancer is the major cause of cancer-related deaths and many cases of Non Small Cell Lung Cancer (NSCLC), a common type of lung cancer, have frequent genetic/oncogenic activation of EGFR, KRAS, PIK3CA, BRAF, and others that drive tumor growth. Some patients though initially respond, but later develop resistance to erlotinib/gefitinib with no option except for cytotoxic therapy. Therefore, development of novel targeted therapeutics is imperative to provide improved survival benefit for NSCLC patients. The mTOR cell survival pathway is activated in naïve, or in response to targeted therapies in NSCLC.MethodsWe have discovered P7170, a small molecule inhibitor of mTORC1/mTORC2/ALK1 and investigated its antitumor efficacy using various in vitro and in vivo models of human NSCLC.ResultsP7170 inhibited the phosphorylation of AKT, S6 and 4EBP1 (substrates for mTORC2 and mTORC1) levels by 80-100% and growth of NSCLC cells. P7170 inhibited anchorage-independent colony formation of NSCLC patient tumor–derived cells subsistent of disease sub-types. The compound also induced apoptosis in NSCLC cell lines. P7170 at a well-tolerated daily dose of 20 mg/kg significantly inhibited the growth of NSCLC xenografts independent of different mutations (EGFR, KRAS, or PIK3CA) or sensitivity to erlotinib. Pharmacokinetic-pharmacodynamic (PK-PD) analysis showed sub-micro molar tumor concentrations along with mTORC1/C2 inhibition.ConclusionsOur results provide evidence of antitumor activity of P7170 in the erlotinib –sensitive and –insensitive models of NSCLC.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-4598-13-259) contains supplementary material, which is available to authorized users.
Highlights
Lung cancer is the major cause of cancer-related deaths and many cases of Non Small Cell Lung Cancer (NSCLC), a common type of lung cancer, have frequent genetic/oncogenic activation of Epidermal growth factor receptor (EGFR), Kirsten rat sarcoma virus (KRAS), PIK3CA, BRAF, and others that drive tumor growth
Utilization of ErbB-3 signaling in response to gefitinib in gefitinib-sensitive cells and IGFIR signaling in gefitinib-resistant cells was shown as a compensatory mechanisms that result in the activation of phosphoinositide 3-kinase (PI3K) in EGFR wild type NSCLC cells [16,17]
The kinase activities of upstream PI3K alpha and mammalian Target Of Rapamycin (mTOR) were inhibited by P7170 (IC50 = 2.2 and 4.4 nM, respectively) but potent biochemical activity of PI3K did not translate in intact cells most likely because of feedback mechanism of mTOR inhibition
Summary
Lung cancer is the major cause of cancer-related deaths and many cases of Non Small Cell Lung Cancer (NSCLC), a common type of lung cancer, have frequent genetic/oncogenic activation of EGFR, KRAS, PIK3CA, BRAF, and others that drive tumor growth. Cell Lung Cancer (NSCLC) cells that promote tumor growth These include, but are not limited to activating mutations or amplification of EGFR, KRAS, PIK3CA, BRAF, and EML4-ALK gene rearrangements and loss of PTEN [2,3,4]. Despite an improved PFS (progression free survival) with EGFRTKI (tyrosine kinase inhibitor) that effectively targets mutant EGFR avidly than wild type, the overall survival remained controversial [9,10] These findings suggest a possible role of other molecular pathways in the NSCLC disease progression. Hyper activation of mTOR signaling frequently occurs in nearly 70% of patient tumors and because mTOR regulate eukaryotic cellular functions such as cell growth, cell survival, metabolism, response to stress, translation, and transcription through multiple pathways [22], several mTOR inhibitors are being discovered and evaluated for cancer therapy. The chemical structure of P7170 is included in the patent # WO-2012007926A1
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