Data from Attenuation of SRC Kinase Activity Augments PARP Inhibitor–mediated Synthetic Lethality in <i>BRCA2</i>-altered Prostate Tumors

Abstract

&lt;div&gt;AbstractPurpose:&lt;p&gt;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 &lt;i&gt;BRCA1/2&lt;/i&gt; and ATM, additional treatments are necessary because the effects are not durable.&lt;/p&gt;Experimental Design:&lt;p&gt;We performed transcriptomic analysis of publicly available mCRPC cases, comparing &lt;i&gt;BRCA2&lt;/i&gt; null with &lt;i&gt;BRCA2&lt;/i&gt; wild-type. We generated &lt;i&gt;BRCA2&lt;/i&gt;-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.&lt;/p&gt;Results:&lt;p&gt;We observed significant enrichment of the SRC signaling pathway in &lt;i&gt;BRCA2&lt;/i&gt;-altered mCRPC. &lt;i&gt;BRCA2&lt;/i&gt;-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 &lt;i&gt;BRCA2&lt;/i&gt;-null prostate cancer cells, mCRPC organoids, and Trp53/Rb1-null prostate cancer cells. Inhibition of SRC signaling by dasatinib augmented DNA damage in &lt;i&gt;BRCA2&lt;/i&gt;-null prostate cancer cells. Moreover, &lt;i&gt;SRC&lt;/i&gt; knockdown increased PARPi sensitivity in &lt;i&gt;BRCA2&lt;/i&gt;-null prostate cancer cells.&lt;/p&gt;Conclusions:&lt;p&gt;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 &lt;i&gt;BRCA2&lt;/i&gt;-null mCRPC.&lt;/p&gt;&lt;/div&gt;