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
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MSK Authors
  1. Michael Morris
    395 Morris
  2. Daniel C Danila
    123 Danila
  3. Wassim Abida
    103 Abida
  4. Ying Zhang Mazzu
    28 Mazzu
  5. Philip Wayne Kantoff
    160 Kantoff
  6. Nabeela Ali Khan
    15 Khan
  7. Mohammad Atiq
    16 Atiq
  8. Rahim Hirani
    5 Hirani