Combined Inhibition of Both p110α and p110β Isoforms of Phosphatidylinositol 3-Kinase Is Required for Sustained Therapeutic Effect in PTEN-Deficient, ER + Breast Cancer.

Purpose: Determine the roles of the PI3K isoforms p110 alpha and p110 beta in PTEN-deficient, estrogen receptor a (ER)-positive breast cancer, and the therapeutic potential of isoform-selective inhibitors. Experimental Design: Anti-estrogen-sensitive and -resistant PTEN-deficient, ER+ human breast cancer cell lines, and mice bearing anti-estrogen-resistant xenografts were treated with the anti-estrogen fulvestrant, the p110 alpha inhibitor BYL719, the p110 beta inhibitor GSK2636771, or combinations. Temporal response to growth factor receptor-initiated signaling, growth, apoptosis, predictive biomarkers, and tumor volumes were measured. Results: p110 beta primed cells for response to growth factor stimulation. Although p110 beta inhibition suppressed cell and tumor growth, dual targeting of p110 alpha/beta enhanced apoptosis and provided sustained tumor response. The growth of antiestrogen-sensitive cells was inhibited by fulvestrant, but fulvestrant inconsistently provided additional therapeutic effects beyond PI3K inhibition alone. Treatment-induced decreases in phosphorylation of AKT and Rb were predictive of therapeutic response. Short-term drug treatment induced tumor cell apoptosis and proliferative arrest to induce tumor regression, whereas long-term treatment only suppressed proliferation to provide durable regression. Conclusions: p110 beta is the dominant PI3K isoform in PTEN-deficient, ER+ breast cancer cells. Upon p110 beta inhibition, p110 alpha did not induce significant reactivation of AKT, but combined targeting of p110 alpha/beta most effectively induced apoptosis in vitro and in vivo and provided durable tumor regression. Because apoptosis and tumor regression occurred early but not late in the treatment course, and proliferative arrest was maintained throughout treatment, p110 alpha/beta inhibitors may be considered short-term cytotoxic agents and long-term cytostatic agents. (C) 2016 AACR.