title: P7170, a novel inhibitor of mTORC1/mTORC2 and Activin receptor-like Kinase 1 (ALK1) inhibits the growth of non small cell lung cancer.
abstract: BACKGROUND
  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. 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.
  
  
  METHODS
  We 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.
  
  
  RESULTS
  P7170 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.
  
  
  CONCLUSIONS
  Our results provide evidence of antitumor activity of P7170 in the erlotinib -sensitive and -insensitive models of NSCLC.
authors.forename: Venkatasubbaiah A
authors.initials: VA
authors.lastname: Venkatesha
authors.forename: Asavari
authors.initials: A
authors.lastname: Joshi
authors.forename: Magesh
authors.initials: M
authors.lastname: Venkataraman
authors.forename: Vinay
authors.initials: V
authors.lastname: Sonawane
authors.forename: Dimple
authors.initials: D
authors.lastname: Bhatia
authors.forename: Prashant
authors.initials: P
authors.lastname: Tannu
authors.forename: Julie
authors.initials: J
authors.lastname: Bose
authors.forename: Sarika
authors.initials: S
authors.lastname: Choudhari
authors.forename: Ankita
authors.initials: A
authors.lastname: Srivastava
authors.forename: Prashant Kumar
authors.initials: PK
authors.lastname: Pandey
authors.forename: Vaibhavi J
authors.initials: VJ
authors.lastname: Lad
authors.forename: Ramachandra
authors.initials: R
authors.lastname: Sangana
authors.forename: Tausif
authors.initials: T
authors.lastname: Ahmed
authors.forename: Anagha
authors.initials: A
authors.lastname: Damre
authors.forename: Vijaykumar
authors.initials: V
authors.lastname: Deore
authors.forename: Bichismita
authors.initials: B
authors.lastname: Sahu
authors.forename: Sanjay
authors.initials: S
authors.lastname: Kumar
authors.forename: Somesh
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Piramal Life Sciences Ltd, # 1 Nirlon Complex, Off: Western Express Highway, Goregaon (East), Mumbai, Maharashtra 400063, India. veena_828@yahoo.com.
authors.forename: Veena R
authors.initials: VR
authors.lastname: Agarwal
mesh_terms: D030301:Activin Receptors, Type II / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D058534:Class I Phosphatidylinositol 3-Kinases; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000494:pharmacology; D000069347:Erlotinib Hydrochloride; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008819:Mice, Nude; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors*; D019869:Phosphatidylinositol 3-Kinases / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000494:pharmacology; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D018631:ras Proteins / Q000494:pharmacology
chemical_list: D030301:Activin Receptors, Type II; D000970:Antineoplastic Agents; D058534:Class I Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D007093:Imidazoles; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines; D011804:Quinolines; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins; C117307:KRAS protein, human; C000601501:P7170 compound; C484760:PIK3CA protein, human; C512478:EGFR protein, human; C425364:ACVRL1 protein, human