Measurement of PIP3 Levels Reveals an Unexpected Role for p110β in Early Adaptive Responses to p110α-Specific Inhibitors in Luminal Breast Cancer

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 of PI3K mediated by p110β 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 p110β inhibitor to BYL719 prevents the PIP3 rebound and induces greater antitumor efficacy in HER2-amplified and PIK3CA mutant cancers. •p110α inhibition leads to reactivation of PI3K signaling via p110β•Restoration of PI3K is reliably determined by measuring PIP3 levels, not p-AKT•Dual inhibition of p110α and β blocks rebound of PIP3 and induces tumor regressions Costa et al. show that PI3Kα inhibition only briefly blocks PI3K signaling even in responsive cancer cells due to PI3Kβ activation. Thus, combined PI3Kα and PI3Kβ inhibition provides greater antitumor efficacy. The authors also find PIP3 to be a better marker of active PI3K signaling than phosphorylated AKT.