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.
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DOI：
10.1158/1078-0432.ccr-20-2483
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发表时间：
2021-03-15
期刊：
影响因子：
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通讯作者：
Kantoff PW
中科院分区：
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作者：
Chakraborty G;Patail NK;Hirani R;Nandakumar S;Mazzu YZ;Yoshikawa Y;Atiq M;Jehane LE;Stopsack KH;Lee GM;Abida W;Morris MJ;Mucci LA;Danila D;Kantoff PW
DNA损伤修复（DDR）途径基因的改变发生在20-25%的转移性去势抵抗性前列腺癌（mCRPC）患者中。尽管聚二磷酸腺苷[ADP]-核糖)聚合酶抑制剂（PARPi）已被证明对因BRCA1/2和ATM突变而携带DDR缺陷的mCRPC患者有益，但由于效果不持久，需要额外的治疗。我们对公开可用的mCRPC病例进行转录组学分析，比较BRCA2-null型和BRCA2野生型。我们使用CRISPR/Cas9生成brca2缺失的前列腺癌细胞，并用PARPi和SRC抑制剂处理这些细胞。我们还评估了三维前列腺癌类器官联合治疗的抗增殖作用。我们观察到SRC信号通路在brca2改变的mCRPC中显著富集。与野生型细胞相比，brca2缺失的前列腺癌细胞系SRC磷酸化增加，对SRC抑制剂（如达沙替尼、博舒替尼和萨拉卡替尼）的敏感性更高。PARPi和SRC抑制剂联合治疗对brca2缺失的前列腺癌细胞、mCRPC类器官和Trp53/ rb1缺失的前列腺癌细胞具有抗增殖和协同作用。达沙替尼对SRC信号的抑制增强了brca2缺失前列腺癌细胞的DNA损伤。此外，SRC敲低增加了brca2缺失前列腺癌细胞中PARPi的敏感性。这项研究表明，SRC激活可能是PARPi耐药的潜在机制，并且SRC抑制剂治疗可能克服这种耐药。我们的临床前研究表明，联合PARPi和SRC抑制剂可能是治疗brca2缺失mCRPC患者的一种有希望的治疗策略。
Alterations in DNA damage repair (DDR) pathway genes occur in 20–25% of men with metastatic castration-resistant prostate cancer (mCRPC). Although poly (adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi) 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. We performed transcriptomic analysis of publicly available mCRPC cases, comparing BRCA2-null to BRCA2 wild type. We generated BRCA2-null prostate cancer cells using CRISPR/Cas9 and treated these cells with PARPi and SRC inhibitors. We also assessed the antiproliferative effects of combination treatment in 3D prostate cancer organoids. 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 (eg, dasatinib, bosutinib, and saracatinib) relative to wild-type cells. Combination treatment with PARPi 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. 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 PARPi and SRC inhibitors may be a promising therapeutic strategy for patients with BRCA2-null mCRPC.