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

Abstract

Purpose Determine the roles of the phosphatidylinositol 3-kinase (PI3K) isoforms p110α and p110β in PTEN-deficient, estrogen receptor α (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 p110α inhibitor BYL719, the p110β inhibitor GSK2636771, or combinations. Temporal response to growth factor receptor-initiated signaling, growth, apoptosis, predictive biomarkers, and tumor volumes were measured. Results p110β primed cells for response to growth factor stimulation. While p110β inhibition suppressed cell and tumor growth, dual targeting of p110α/β enhanced apoptosis and provided sustained tumor response. The growth of anti-estrogen-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, while long-term treatment only suppressed proliferation to provide durable regression. Conclusions p110β is the dominant PI3K isoform in PTEN-deficient, ER+ breast cancer cells. Upon p110β inhibition, p110α did not induce significant reactivation of AKT, but combined targeting of p110α/β most effectively induced apoptosis in vitro and in vivo and provided durable tumor regression. Since apoptosis and tumor regression occurred early but not late in the treatment course, and proliferative arrest was maintained throughout treatment, p110α/β inhibitors may be considered short-term cytotoxic agents and long-term cytostatic agents.

The PI3K Pathway in Human Disease

“…Similar results were reported by Baselga and colleagues (Schwartz et al, 2015), who found that treatment with a selective p110β inhibitor led to transient suppression of, followed by a significant rebound in phospho-AKT levels, which were attributed to the upregulation of the IGFR1-IRS1-p110α signaling cascade. Similarly, combined treatment with p110α- and p110β-selective inhibitors caused greater tumor growth inhibition in both a PTEN -null prostate cancer and ER + breast cancer models (Hosford et al, 2016). In PTEN -deficient, ER+ breast cancer xenografts, treatment with the triple combination of fulvestrant (a selective estrogen receptor degrader) together with inhibitors of p110α and p110β was required to trigger maximal, sustained tumor regressions.…”

Cytokine sensitivity screening highlights BMP4 pathway signaling as a therapeutic opportunity in ER + breast cancer

“…These results were surprising, as the main mechanism of anti-cancer action of anti-estrogens and CDK4/6 i is thought to involve inhibition of cell-cycle progression (58,59). However, evidence suggests that multiple inhibitors that converge at the level of (blocking) P-Rb can synergize despite targeting seemingly redundant pathways (60)(61)(62)(63). In addition, antiproliferative cytokines, such as TGF-b, can increase the threshold for CDK4/6 activation and synergize with CDK4/6 i to induce more complete cell-cycle arrest (64).…”

Everolimus versus alpelisib in advanced hormone receptor-positive HER2-negative breast cancer: targeting different nodes of the PI3K/AKT/mTORC1 pathway with different clinical implications

“…Tumor suppressor enzymes prevent uncontrolled activation of the PI3K/AKT/mTORC1 cascade at different levels: among them, PTEN counteracts PI3K activity by dephosphorylating PIP3 to PIP2, while LKB1 indirectly inhibits mTORC1 via AMP-activated protein kinase (AMPK)-mediated activation of TSC1/2 [22,23].…”