RT Journal Article
SR Electronic
T1 Attenuation of SRC Kinase Activity Augments PARP Inhibitor–mediated Synthetic Lethality in <em>BRCA2</em>-altered Prostate Tumors
JF Clinical Cancer Research
JO Clin Cancer Res
FD American Association for Cancer Research
DO 10.1158/1078-0432.CCR-20-2483
A1 Chakraborty, Goutam
A1 Patail, Nabeela Khan
A1 Hirani, Rahim
A1 Nandakumar, Subhiksha
A1 Mazzu, Ying Z.
A1 Yoshikawa, Yuki
A1 Atiq, Mohammad
A1 Jehane, Lina E.
A1 Stopsack, Konrad H.
A1 Lee, Gwo-Shu Mary
A1 Abida, Wassim
A1 Morris, Michael J.
A1 Mucci, Lorelei A.
A1 Danila, Daniel
A1 Kantoff, Philip W.
YR 2020
UL http://clincancerres.aacrjournals.org/content/early/2021/01/21/1078-0432.CCR-20-2483.abstract
AB Purpose: 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 BRCA1/2 and ATM, additional treatments are necessary because the effects are not durable.Experimental Design: We performed transcriptomic analysis of publicly available mCRPC cases, comparing BRCA2 null with BRCA2 wild-type. We generated BRCA2-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.Results: 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 (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 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.Conclusions: 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 BRCA2-null mCRPC.