Dynamic pro-survival signaling mediates resistance to androgen receptor targeted therapy in ARv7 splice variant expressing prostate cancer models.
Pilling A, and Hwang C. Dynamic pro-survival signaling mediates resistance to androgen receptor targeted therapy in ARv7 splice variant expressing prostate cancer models. Cancer Res 2018; 78(13)
Patient survival rates for metastatic prostate cancer are limited by therapeutic failure and disease progression. Treatment of castrate resistant prostate cancer (CRPC) remains a clinical challenge as current treatment options offer modest benefit and are not curative. Second generation androgen axis inhibitors such as enzalutamide and abiraterone acetate provide initial clinical benefit for patients. However, responses are not durable and disease progression is inevitable, resulting in limited patient survival. Several mechanisms of resistance have been identified that relate to persistent AR signaling including AR splice variants (AR-Vs) which encode an AR protein lacking the ligand binding domain (LBD). Since we have demonstrated that enzalutamide induces an apoptotic response in sensitive prostate tumor cells, we hypothesized that anti-apoptotic signaling is a critical mechanism of resistance to AR-targeted therapy in resistant tumor cell populations. Using 22Rv1 cells, a cell line model that expresses high levels of ARv7, and cell lines that express low or no AR-Vs, we demonstrate differential activation of intrinsic/Bcl2-mediated apoptosis signaling in response to enzalutamide. Specifically, in 22Rv1 cells we demonstrate robust induction of anti-apoptotic signaling including increased Bcl-2 and Mcl-1 expression and inactivation of the apoptosis sensitizer Bad in response to enzalutamide, where this signaling is opposed in enzalutamide-sensitive cells. Analysis of potential upstream regulators revealed phosphorylation and activation of Akt through PI3K signaling in the ARV-expressing 22Rv1 cells in response to AR antagonism. Pharmacological inhibition of PI3K/Akt signaling in combination with enzalutamide prevented upregulation of Mcl-1 and inactivation of Bad, thus lowering the apoptotic threshold and sensitizing 22Rv1 cells to enzalutamide. In conclusion, this data demonstrates active engagement of pro-survival kinase signaling that mediates an increased apoptotic threshold in response to AR-directed therapy. Therefore, resistance to AR-directed therapy in ARV-expressing tumors may extend beyond the recognized mechanisms of treatment failure (i.e. lack of LBD for drug binding, constitutive AR transcriptional activity) and involve dynamic anti-apoptosis signaling. We demonstrate that strategies that lower the apoptotic threshold can increase sensitivity to AR antagonist in ARV-expressing cells and represents a novel therapeutic approach with potential to manage or overcome therapy resistance in this lethal form of prostate cancer.