title: Characterization of the novel and specific PI3Kα inhibitor NVP-BYL719 and development of the patient stratification strategy for clinical trials.
abstract: Somatic PIK3CA mutations are frequently found in solid tumors, raising the hypothesis that selective inhibition of PI3Kα may have robust efficacy in PIK3CA-mutant cancers while sparing patients the side-effects associated with broader inhibition of the class I phosphoinositide 3-kinase (PI3K) family. Here, we report the biologic properties of the 2-aminothiazole derivative NVP-BYL719, a selective inhibitor of PI3Kα and its most common oncogenic mutant forms. The compound selectivity combined with excellent drug-like properties translates to dose- and time-dependent inhibition of PI3Kα signaling in vivo, resulting in robust therapeutic efficacy and tolerability in PIK3CA-dependent tumors. Novel targeted therapeutics such as NVP-BYL719, designed to modulate aberrant functions elicited by cancer-specific genetic alterations upon which the disease depends, require well-defined patient stratification strategies in order to maximize their therapeutic impact and benefit for the patients. Here, we also describe the application of the Cancer Cell Line Encyclopedia as a preclinical platform to refine the patient stratification strategy for NVP-BYL719 and found that PIK3CA mutation was the foremost positive predictor of sensitivity while revealing additional positive and negative associations such as PIK3CA amplification and PTEN mutation, respectively. These patient selection determinants are being assayed in the ongoing NVP-BYL719 clinical trials.
authors.affiliation: Authors' Affiliations: Novartis Institutes for BioMedical Research, Disease Area Oncology; Novartis Institutes for BioMedical Research, Global Discovery Chemistry; Novartis Institutes for BioMedical Research, Center for Proteomic Chemistry; Novartis Pharma AG, Oncology Translational Medicine, Basel, Switzerland; Novartis Pharma AG, Oncology Translational Medicine; Novartis Institutes for BioMedical Research, Developmental and Molecular Pathways, Cambridge, Massachusetts; and Novartis Institutes for BioMedical Research, Developmental and Molecular Pathways, Shangai, China.
authors.forename: Christine
authors.initials: C
authors.lastname: Fritsch
authors.forename: Alan
authors.initials: A
authors.lastname: Huang
authors.forename: Christian
authors.initials: C
authors.lastname: Chatenay-Rivauday
authors.forename: Christian
authors.initials: C
authors.lastname: Schnell
authors.forename: Anupama
authors.initials: A
authors.lastname: Reddy
authors.forename: Manway
authors.initials: M
authors.lastname: Liu
authors.forename: Audrey
authors.initials: A
authors.lastname: Kauffmann
authors.forename: Daniel
authors.initials: D
authors.lastname: Guthy
authors.forename: Dirk
authors.initials: D
authors.lastname: Erdmann
authors.forename: Alain
authors.initials: A
authors.lastname: De Pover
authors.forename: Pascal
authors.initials: P
authors.lastname: Furet
authors.forename: Hui
authors.initials: H
authors.lastname: Gao
authors.forename: Stephane
authors.initials: S
authors.lastname: Ferretti
authors.forename: Youzhen
authors.initials: Y
authors.lastname: Wang
authors.forename: Joerg
authors.initials: J
authors.lastname: Trappe
authors.forename: Saskia M
authors.initials: SM
authors.lastname: Brachmann
authors.forename: Sauveur-Michel
authors.initials: SM
authors.lastname: Maira
authors.forename: Christopher
authors.initials: C
authors.lastname: Wilson
authors.forename: Markus
authors.initials: M
authors.lastname: Boehm
authors.forename: Carlos
authors.initials: C
authors.lastname: Garcia-Echeverria
authors.forename: Patrick
authors.initials: P
authors.lastname: Chene
authors.forename: Marion
authors.initials: M
authors.lastname: Wiesmann
authors.forename: Robert
authors.initials: R
authors.lastname: Cozens
authors.forename: Joseph
authors.initials: J
authors.lastname: Lehar
authors.forename: Robert
authors.initials: R
authors.lastname: Schlegel
authors.forename: Giorgio
authors.initials: G
authors.lastname: Caravatti
authors.forename: Francesco
authors.initials: F
authors.lastname: Hofmann
authors.forename: William R
authors.initials: WR
authors.lastname: Sellers
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051381:Rats; D013844:Thiazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D058534:Class I Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013844:Thiazoles; C585539:Alpelisib; C484760:PIK3CA protein, human