P7170, a novel inhibitor of mTORC1/mTORC2 and Activin receptor-like Kinase 1 (ALK1) inhibits the growth of non small cell lung cancer

Molecular Cancer

Research

Vijaykumar Deore¹  Vinay Sonawane¹  Ankita Srivastava¹  Julie Bose¹  Sarika Choudhari¹  Prashant Tannu¹  Anagha Damre¹  Sanjay Kumar¹  Venkatasubbaiah A Venkatesha¹  Prashant Kumar Pandey¹  Magesh Venkataraman¹  Somesh Sharma¹  Asavari Joshi¹  Vaibhavi J Lad¹  Veena R Agarwal¹  Dimple Bhatia¹  Ramachandra Sangana¹  Tausif Ahmed¹  Bichismita Sahu¹ 

[1] Piramal Life Sciences Ltd. # 1 Nirlon Complex, Off: Western Express Highway, Goregaon (East), 400063, Mumbai, Maharashtra, India;

关键词: NSCLC;    mTORC1;    mTORC2;    STAT3;    PI3K;    EGFR-TKI;    Tumor xenograft;    Targeted therapeutics;    PK-PD;   

DOI  :  10.1186/1476-4598-13-259

 received in 2014-06-09, accepted in 2014-11-24,  发布年份 2014

来源: Springer

【 摘 要 】

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.

【 授权许可】

Unknown   
© Venkatesha et al.; licensee BioMed Central. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.