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Attenuation of SRC Kinase Activity Augments PARP Inhibitor-Mediated Synthetic Lethality in BRCA2-Altered Prostate Tumors - Beyond the Abstract

Deleterious alterations in genes that are directly or indirectly associated with DNA damage repair (DDR) are enriched in lethal aggressive prostate cancer (PC). About 25–30% of patients with metastatic castration-resistant prostate cancer (mCRPC) harbor loss-of-function alterations in DDR genes and respond to current androgen receptor (AR) inhibitors.1 Recently, PARP inhibitors (PARPi) have shown promise in mCRPC patients harboring DDR pathway defects, in particular, but not exclusively BRCA2-altered tumors, leading to a breakthrough designation for PARPi by the FDA in this patient population.2,3 Despite responses, resistance is common, and treatment modalities for PARPi-resistant patients are limited.4 Therefore, an urgent unmet need is to develop well-tolerated, targeted combination treatments of PARPi with other agents that create synergy that would allow more durable responses to PARPi and improve the survival of mCRPC patients.

Earlier, we reported that a large fraction of primary and metastatic PCs exhibit chromosomal deletions (homozygous but more frequently heterozygous) of BRCA2, which was previously unrecognized. The tumor suppressor RB1 is located on chromosome 13q (Chr13q) near BRCA2. We also showed that patients with primary PC who have BRCA2-RB1 co-deletion have significantly shorter biochemical recurrence-free survival than patients with deletion of neither or RB1 deletions alone. In contrast, deletion of BRCA2 without RB1 is rare.5

Our current study investigates the signaling pathways involved in the phenotype associated with BRCA2 loss to identify potential therapeutic targets for such cases.6 We found a strong enrichment of the SRC signaling pathway in BRCA2-altered tumors, and our analysis also identified dasatinib, a pharmacological SRC-inhibitor, as a potential agent for BRCA2-deleted mCRPC tumors. As described in our manuscript, we showed that BRCA2 altered PC cells exhibit growth inhibition in response to SRCinhibitors (e.g., dasatinib, saracatinib, and bosutinib). Additionally, significant up-regulation in the SRCsignaling pathway was noted in human PC cell lines and patients-derived organoids that harbor genomic deletion of BRCA2.6

Combining PARPi with other agents that synergize would allow higher response rates and greater durability. We used our experimental cell line systems and examined the effects of dasatinib combined with pharmacological PARPi (olaparib and talazoparib). We showed that co-inhibition of PARP and SRC pathways exhibit strong inhibition of cell growth in BRCA2 altered PC cell lines and organoids compared to either inhibitor alone, indicating drug synergy.6 Our study also suggests that SRC activation may be a possible mechanism of PARPi resistance in PC; treatment with SRC-inhibitors may overcome this resistance. Additionally, we reported that in PC cell lines (human and mouse) with intact DDR pathways that harbor defective tumor suppressors P53 and RB1, only the combination of PARPi and SRCi showed growth inhibition, with minimal decrease in cell proliferation with either agent alone.6

Currently, there are many studies of PARPi in mCRPC, and some that test PARPi in earlier disease states of men with castration-sensitive metastatic prostate cancer or even in neoadjuvant settings. In our preclinical models, the addition of SRCi to PARPi in DDR defective tumors has enhanced activity and may rescue secondary resistance developed during prior treatment with PARPi. Our results are promising and suggest mCRPC patients with BRCA2 mutations would benefit from a combination treatment of PARPi and Src-inhibitors, and further exploration via clinical trials is warranted. Our work also demonstrated synergy of PARPi and SRCi in PC cell lines with alterations in tumor suppressors such as P53 or RB1, where we believe this combination has great potential in mCRPC patients

Written by: Goutam Chakraborty & Philip Kantoff, Department of Medicine; Memorial Sloan Kettering Cancer Center, New York

References: 

  1. Abida W, Cyrta J, Heller G, Prandi D, Armenia J, Coleman I, et al. Genomic correlates of clinical outcome in advanced prostate cancer. Proc Natl Acad Sci U S A 2019;116(23):11428-36 doi 10.1073/pnas.1902651116.
  2. Abida W, Patnaik A, Campbell D, Shapiro J, Bryce AH, McDermott R, et al. Rucaparib in Men With Metastatic Castration-Resistant Prostate Cancer Harboring a BRCA1 or BRCA2 Gene Alteration. J Clin Oncol 2020;38(32):3763-72 doi 10.1200/JCO.20.01035.
  3. de Bono J, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, et al. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med 2020;382(22):2091-102 doi 10.1056/NEJMoa1911440.
  4. Mateo J, Lord CJ, Serra V, Tutt A, Balmana J, Castroviejo-Bermejo M, et al. A decade of clinical development of PARP inhibitors in perspective. Ann Oncol 2019;30(9):1437-47 doi 10.1093/annonc/mdz192.
  5. Chakraborty G, Armenia J, Mazzu YZ, Nandakumar S, Stopsack KH, Atiq MO, et al. Significance of BRCA2 and RB1 Co-loss in Aggressive Prostate Cancer Progression. Clin Cancer Res 2020;26(8):2047-64 doi 10.1158/1078-0432.CCR-19-1570.
  6. Chakraborty G, Patail NK, Hirani R, Nandakumar S, Mazzu YZ, Yoshikawa Y, et al. Attenuation of SRC Kinase Activity Augments PARP Inhibitor-mediated Synthetic Lethality in BRCA2-altered Prostate Tumors. Clin Cancer Res 2021;27(6):1792-806 doi 10.1158/1078-0432.CCR-20-2483.

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