Alterations in DNA damage repair (DDR) pathway genes occur in 20-25% of men with metastatic castration-resistant prostate cancer (mCRPC). Although poly (adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi) have been shown to benefit men with mCRPC harboring DDR defects due to mutations in BRCA1/2 and ATM, additional treatments are necessary because the effects are not durable.
We performed transcriptomic analysis of publicly available mCRPC cases, comparing BRCA2-null to BRCA2 wild type. We generated BRCA2-null prostate cancer cells using CRISPR/Cas9 and treated these cells with PARPi 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 BRCA2-altered mCRPC. BRCA2-null prostate cancer cell lines had increased SRC phosphorylation and higher sensitivity to SRC inhibitors (eg, dasatinib, bosutinib, and saracatinib) relative to wild-type cells. Combination treatment with PARPi and SRC inhibitors was antiproliferative and had a synergistic effect in BRCA2-null prostate cancer cells, mCRPC organoids, and Trp53/Rb1-null prostate cancer cells. Inhibition of SRC signaling by dasatinib augmented DNA damage in BRCA2-null prostate cancer cells. Moreover, SRC knockdown increased PARPi sensitivity in BRCA2-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 PARPi and SRC inhibitors may be a promising therapeutic strategy for patients with BRCA2-null mCRPC.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2020 Dec 17 [Epub ahead of print]
Goutam Chakraborty, Nabeela Khan Patail, Rahim Hirani, Subhiksha Nandakumar, Ying Z Mazzu, Yuki Yoshikawa, Mohammad O Atiq, Lina Jehane, Konrad H Stopsack, Gwo-Shu Mary Lee, Wassim Abida, Michael J Morris, Lorelei A Mucci, Daniel C Danila, Philip W Kantoff
Medicine, Memorial Sloan Kettering Cancer Center., Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center., Department of Medicine, Memorial Sloan Kettering Cancer Center., Medicine, Baylor College of Medicine., Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School., Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College., Department of Epidemiology, Harvard T.H. Chan School of Public Health., Medicine(Genitourinary Oncology Service), Memorial Sloan Kettering Cancer Center., Department of Medicine, Memorial Sloan Kettering Cancer Center .
PubMed http://www.ncbi.nlm.nih.gov/pubmed/33334906