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Measurement of PIP Levels Reveals an Unexpected Role for p110beta in Early Adaptive Responses to p110alpha-Specific Inhibitors in Luminal Breast Cancer

Costa, C and Ebi, H and Martini, M and Beausoleil, SA and Faber, AC and Jakubik, CT and Huang, A and Wang, Y and Nishtala, M and Hall, B and Rikova, K and Zhao, J and Hirsch, E and Benes, CH and Engelman, JA (2014) Measurement of PIP Levels Reveals an Unexpected Role for p110beta in Early Adaptive Responses to p110alpha-Specific Inhibitors in Luminal Breast Cancer. Cancer Cell.

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 p110alpha inhibition is mitigated by rapid re-accumulation of the PI3K product PIP3 produced by the p110beta isoform. Importantly, the reactivation of PI3K mediated by p110beta 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 p110beta inhibitor to BYL719 prevents the PIP3 rebound and induces greater antitumor efficacy in HER2-amplified and PIK3CA mutant cancers

Item Type: Article
Additional Information: NIBR author: Huang, A institute: NIBR contributor address:
Date Deposited: 13 Oct 2015 13:11
Last Modified: 13 Oct 2015 13:11
URI: https://oak.novartis.com/id/eprint/24937

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