Small Molecule Therapeutics Characterization of the Novel and Specific PI3Ka Inhibitor NVP-BYL719 and Development of the Patient Stratification Strategy for Clinical Trials

Somatic PIK3CA mutations are frequently found in solid tumors, raising the hypothesis that selective inhibition of PI3Kamay 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 PI3Ka and its most common oncogenic mutant forms. The compound selectivity combined with excellent drug-like properties translates to doseand time-dependent inhibition of PI3Ka 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 uponwhich 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 PTENmutation, respectively. These patient selection determinants are being assayed in the ongoing NVP-BYL719 clinical trials.Mol Cancer Ther; 13(5); 1–13. 2014 AACR.