Co-Inhibition of p110α and p110β Is Required for Sustained PI3K Suppression

Aberrant activation of the phosphatidylinositol 3-kinase (PI3K) pathway by PIK3CA mutation, HER2 amplification, or PTEN deletion occurs frequently in solid tumors. Isoform-specific inhibitors of the PI3K catalytic subunits p110α, p110β, and p110δ are in clinical development, but it remains unclear which inhibitors would be most effective in different contexts. In the course of testing breast cancer cell line sensitivity to the p110α inhibitor BYL719, Costa and colleagues found that BYL719 only transiently suppressed PI3K-dependent phosphatidylinositol (3,4,5) triphosphate (PIP₃) production in HER2-amplified or PIK3CA-mutant cells and AKT phosphorylation in HER2-amplified cells. p110β was responsible for the rebound of PIP₃ production and AKT phosphorylation and was reactivated in the presence of BYL719 by the release of p110α-dependent negative feedback regulation of ERBB3 in HER2-amplified cells and IGF1R and ERBB3 in PIK3CA-mutant cells. Importantly, combined treatment of HER2-amplified or PIK3CA-mutant breast cancer cells with a combination of p110α- and p110β-selective inhibitors led to greater PI3K pathway suppression than either agent alone and was necessary to induce tumor regression. In the setting of PTEN-mutant prostate cancer, which is p110β dependent, Schwartz and colleagues showed that inhibition of p110β with AZD8186 led to relief of feedback inhibition of IGF1R and p110α, which in turn drove PI3K signaling. Co-inhibition of p110α and p110β was required for complete suppression of AKT signaling, but failed to arrest tumor growth in vivo. Consistent with the previous finding that reciprocal feedback inhibition exists between the PI3K and androgen receptor (AR) pathways, p110β inhibition activated AR, and only the combination of p110α, p110β, and AR inhibition led to significant tumor regression. These complementary studies highlight adaptive resistance mechanisms that may potentially limit the effectiveness of single-agent p110α or p110β inhibitor therapy and provide support for simultaneously targeting each isoform in PI3K-driven cancers to avoid potential toxicity associated with pan-PI3K inhibition and allow maximal inhibition of each isoform.

Costa C, Ebi H, Martini M, Beausoleil SA, Faber AC, Jakubik CT, et al. Measurement of PIP3 levels reveals an unexpected role for p110β in early adaptive responses to p110α-specific inhibitors in luminal breast cancer. Cancer Cell 2015;27:97–108.

Schwartz S, Wongvipat J, Trigwell CB, Hancox U, Carver BS, Rodrik-Outmezguine V, et al. Feedback suppression of PI3Kα signaling in PTEN-mutated tumors is relieved by selective inhibition of PI3Kβ. Cancer Cell 2015;27:109–22.

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