Abstract A2: Selective inhibition of mTORC1/mTORC2 sensitizes prostate cancer cells to the effects of AR or IGF-1R/IR antagonists, providing an approach to overcome intrinsic mechanisms of resistance

Abstract Prostate cancer is a complex disease primarily characterized by dependence on androgen receptor (AR) signaling. Androgen deprivation therapy is efficacious; however, prostate tumors which initially respond to castration or androgen antagonists eventually progress. These castration-resistant tumors may develop hypersensitivity to low levels of androgens and AR overexpression or may adapt to rely on alternate signaling pathways such as the PI3K/mTOR axis. Deregulation of the PI3K/mTOR axis is a feature of prostate cancer, as evidenced by the fact that 40% of primary and 70% of metastatic prostate tumors exhibit loss of the tumor suppressor PTEN. Recent publications have shown that crosstalk between the AR and PTEN/PI3K/mTOR pathways plays a role in prostate cancer development and progression (1,2). Building upon these data, we evaluated the effects of ASP7486 (OSI-027), a selective inhibitor of mTORC1/mTORC2 as monotherapy and combined with bicalutamide, an androgen receptor antagonist. ASP7486 inhibited proliferation across a panel of prostate cancer cell lines, including those refractory to bicalutamide, supporting the hypothesis that tumors which have acquired androgen independence may rely upon mTOR signaling for survival. ASP7486 but not rapamycin, an allosteric mTORC1 inhibitor, induced apoptosis, implying that mTORC2 signaling is an important regulator of survival in prostate cancer. ASP7486, but not rapamycin, significantly upregulated AR expression which may serve to sensitize cells to the effect of an antiandrogen while limiting sensitivity to mTOR inhibition as a monotherapy. Consistent with this, the combination of ASP7486 and bicalutamide synergistically inhibited proliferation in vitro. In prostate tumors which have acquired resistance to androgen antagonists, activation of alternate RTKs may provide a survival mechanism in the absence of functional AR. PI3K pathway alterations and increased expression of IFG-1R are observed in castrate-resistant tumors (3,4). Treatment of prostate cancer cells with ASP7486 leads to increased phosphorylation of multiple RTKs, including IGF-1R and IR. We reasoned that ASP7486-mediated activation of IGF-1R and IR would sensitize these cells to the effects of OSI-906, a selective IGF-1R/IR inhibitor. The combination of ASP7486 and OSI-906, a selective inhibitor of IGF-1R/IR, synergistically inhibited proliferation and induced apoptosis. The combination of the two drugs provided greater inhibition of key signaling effectors than either monotherapy. These effects are not limited to prostate cancer. We have observed ASP7486-induced upregulation of RTK expression and phosphorylation in multiple tumor types, and the combination of ASP7486 and OSI-906 synergistically inhibited proliferation in the majority of cell lines tested. Together these data demonstrate that combinations of ASP7486 with targeted inhibitors can attenuate crosstalk between signaling networks and provide synergistic efficacy in vitro. The importance of AR and IGF-1R/PI3K/mTOR signaling in prostate cancer provides a rationale for targeting the disease and its intrinsic mechanisms of resistance with inhibitors of these pathways or in combination.