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Characterization of the novel and specific PI3Kα inhibitor NVP-BYL719 and development of the patient stratification strategy for clinical trials.
- Source :
-
Molecular cancer therapeutics [Mol Cancer Ther] 2014 May; Vol. 13 (5), pp. 1117-29. Date of Electronic Publication: 2014 Mar 07. - Publication Year :
- 2014
-
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.
- Subjects :
- Animals
Antineoplastic Agents pharmacokinetics
Cell Line, Tumor
Class I Phosphatidylinositol 3-Kinases
Disease Models, Animal
Drug Evaluation, Preclinical
Drug Resistance, Neoplasm genetics
Female
Humans
Inhibitory Concentration 50
Mice
Mutation
Neoplasms drug therapy
Neoplasms genetics
Neoplasms metabolism
PTEN Phosphohydrolase genetics
PTEN Phosphohydrolase metabolism
Phosphatidylinositol 3-Kinases genetics
Rats
Thiazoles pharmacokinetics
Xenograft Model Antitumor Assays
Antineoplastic Agents pharmacology
Phosphoinositide-3 Kinase Inhibitors
Thiazoles pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1538-8514
- Volume :
- 13
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Molecular cancer therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 24608574
- Full Text :
- https://doi.org/10.1158/1535-7163.MCT-13-0865