2. Academic Validation
  3. Characterization of the novel and specific PI3Kα inhibitor NVP-BYL719 and development of the patient stratification strategy for clinical trials

Characterization of the novel and specific PI3Kα inhibitor NVP-BYL719 and development of the patient stratification strategy for clinical trials

  • Mol Cancer Ther. 2014 May;13(5):1117-29. doi: 10.1158/1535-7163.MCT-13-0865.
Christine Fritsch 1,  Alan Huang,  Christian Chatenay-Rivauday,  Christian Schnell,  Anupama Reddy,  Manway Liu,  Audrey Kauffmann,  Daniel Guthy,  Dirk Erdmann,  Alain De Pover,  Pascal Furet,  Hui Gao,  Stephane Ferretti,  Youzhen Wang,  Joerg Trappe,  Saskia M Brachmann,  Sauveur-Michel Maira,  Christopher Wilson,  Markus Boehm,  Carlos Garcia-Echeverria,  Patrick Chene,  Marion Wiesmann,  Robert Cozens,  Joseph Lehar,  Robert Schlegel,  Giorgio Caravatti,  Francesco Hofmann,  William R Sellers
Affiliations

Affiliation

  • 1 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.
PMID: 24608574 DOI: 10.1158/1535-7163.MCT-13-0865
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.

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