Synapse - Attenuation of SRC kinase activity augments PARP inhibitor-mediated synthetic lethality in BRCA2-altered prostate tumors

Attenuation of SRC kinase activity augments PARP inhibitor-mediated synthetic lethality in BRCA2-altered prostate tumors Journal Article

Authors:	Chakraborty, G.; Khan Patail, N.; Hirani, R.; Nandakumar, S.; Mazzu, Y. Z.; Yoshikawa, Y.; Atiq, M.; Jehane, L. E.; Stopsack, K. H.; Lee, G. S. M.; Abida, W.; Morris, M. J.; Mucci, L. A.; Danila, D.; Kantoff, P. W.
Article Title:	Attenuation of SRC kinase activity augments PARP inhibitor-mediated synthetic lethality in BRCA2-altered prostate tumors
Abstract:	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 withBRCA2-nullmCRPC.
Keywords:	metastasis; phosphorylation; men; growth-factor; activation; defects; combination; family kinases; cancer; dna-repair pathways
Journal Title:	Clinical Cancer Research
Volume:	27
Issue:	6
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Date Published:	2021-03-15
Start Page:	1792
End Page:	1806
Language:	English
ACCESSION:	WOS:000630142100020
DOI:	10.1158/1078-0432.Ccr-20-2483
PROVIDER:	wos
PMCID:	PMC7956224
PUBMED:	33334906
Notes:	Article -- Source: Wos