Attenuation of SRC Kinase Activity Augments PARP Inhibitor-mediated Synthetic Lethality in <i>BRCA2</i>-altered Prostate Tumors.

Abstract

Alterations in DNA damage repair (DDR) pathway genes occur in 20%-25% of men with metastatic castration-resistant prostate cancer (mCRPC). Although PARP inhibitors (PARPis) have been shown to benefit men with mCRPC harboring DDR defects due to mutations in <i>BRCA1/2</i> and ATM, additional treatments are necessary because the effects are not durable. We performed transcriptomic analysis of publicly available mCRPC cases, comparing <i>BRCA2</i> null with <i>BRCA2</i> wild-type. We generated <i>BRCA2</i>-null prostate cancer cells using CRISPR/Cas9 and treated these cells with PARPis and SRC inhibitors. We also assessed the antiproliferative effects of combination treatment in 3D prostate cancer organoids. We observed significant enrichment of the SRC signaling pathway in <i>BRCA2</i>-altered mCRPC. <i>BRCA2</i>-null prostate cancer cell lines had increased SRC phosphorylation and higher sensitivity to SRC inhibitors (e.g., dasatinib, bosutinib, and saracatinib) relative to wild-type cells. Combination treatment with PARPis and SRC inhibitors was antiproliferative and had a synergistic effect in <i>BRCA2</i>-null prostate cancer cells, mCRPC organoids, and Trp53/Rb1-null prostate cancer cells. Inhibition of SRC signaling by dasatinib augmented DNA damage in <i>BRCA2</i>-null prostate cancer cells. Moreover, <i>SRC</i> knockdown increased PARPi sensitivity in <i>BRCA2</i>-null prostate cancer cells. This work suggests that SRC activation may be a potential mechanism of PARPi resistance and that treatment with SRC inhibitors may overcome this resistance. Our preclinical study demonstrates that combining PARPis and SRC inhibitors may be a promising therapeutic strategy for patients with <i>BRCA2</i>-null mCRPC.