Targeting CDK7 Enhances the Antitumor Efficacy of Enzalutamide in Androgen Receptor-Positive Triple-Negative Breast Cancer by Inhibiting c-MYC-mediated Tumorigenesis

Abstract

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer. Among TNBC subtypes, the luminal androgen receptor (LAR) subtype expresses high levels of androgen receptor (AR) and generally responds poorly to neoadjuvant chemotherapy. AR has been reported as a promising therapeutic target for the LAR TNBC subtype. In this study, we evaluated the preclinical antitumor efficacy of enzalutamide, an AR inhibitor, in TNBC. Enzalutamide had moderate antiproliferative activity against AR-positive (AR+) TNBC cells (IC50 > 15 μmol/L). To enhance its antitumor efficacy, we performed high-throughput kinome RNAi screening and identified the cell cycle pathway as a potential target. Inhibition of cell cycle progression using the cyclin-dependent kinase 7 inhibitor KRLS-017 showed a synergistic antiproliferative effect with enzalutamide in AR+ LAR MDA-MB-453 and SUM185 TNBC cells. Downstream target analysis revealed that the enzalutamide and KRLS-017 combination dramatically reduced c-MYC expression at both mRNA and protein levels. c-MYC knockdown significantly suppressed growth of MDA-MB-453 and SUM185 cells to a degree comparable with that of enzalutamide and KRLS-017 combination treatment, whereas c-MYC overexpression reversed the synergistic effect. An enhancement in inhibition of tumor growth and suppression of c-MYC expression was further confirmed when enzalutamide was combined with KRLS-017 in an MDA-MB-453 mouse model. Our study suggests that KRLS-017 enhances the antitumor efficacy of enzalutamide by inhibiting c-MYC-mediated tumorigenesis and presents a potential new approach for treating AR+ LAR TNBC.