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Measurement of PIP3 levels reveals an unexpected role for p110? in early adaptive responses to p110?-specific inhibitors in luminal breast cancer.


ABSTRACT: BYL719, which selectively inhibits the alpha isoform of the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (p110a), is currently in clinical trials for the treatment of solid tumors, especially luminal breast cancers with PIK3CA mutations and/or HER2 amplification. This study reveals that, even among these sensitive cancers, the initial efficacy of p110? inhibition is mitigated by rapid re-accumulation of the PI3K product PIP3 produced by the p110? isoform. Importantly, the reactivation of PI3K mediated by p110? does not invariably restore AKT phosphorylation, demonstrating the limitations of using phospho-AKT as a surrogate to measure PI3K activation. Consistently, we show that the addition of the p110? inhibitor to BYL719 prevents the PIP3 rebound and induces greater antitumor efficacy in HER2-amplified and PIK3CA mutant cancers.

SUBMITTER: Costa C 

PROVIDER: S-EPMC4745884 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Measurement of PIP3 levels reveals an unexpected role for p110β in early adaptive responses to p110α-specific inhibitors in luminal breast cancer.

Costa Carlotta C   Ebi Hiromichi H   Martini Miriam M   Beausoleil Sean A SA   Faber Anthony C AC   Jakubik Charles T CT   Huang Alan A   Wang Youzhen Y   Nishtala Madhuri M   Hall Ben B   Rikova Klarisa K   Zhao Jean J   Hirsch Emilio E   Benes Cyril H CH   Engelman Jeffrey A JA  

Cancer cell 20141224 1


BYL719, which selectively inhibits the alpha isoform of the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (p110a), is currently in clinical trials for the treatment of solid tumors, especially luminal breast cancers with PIK3CA mutations and/or HER2 amplification. This study reveals that, even among these sensitive cancers, the initial efficacy of p110α inhibition is mitigated by rapid re-accumulation of the PI3K product PIP3 produced by the p110β isoform. Importantly, the reactivation  ...[more]

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