Exploiting DNA Repair Defect in Triple Negative Brest Cancer Using CDK Inhibition Strategy

C. Velázquez, Esin Orhan, I. Tabet, Lise Fenou, Laura Boudarel, C. Theillet
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Abstract

Triple-negative breast cancer (TNBC), representing 15% of breast carcinomas, is an aggressive breast cancer subtype with a high probability of metastasis and limited treatment options. Noticeably, BRCA-deficiency occurs in 25% of the TNBCs and results in deficient homologous recombination (HR) repair. Interestingly, PARP inhibitors (PARPi) have shown synthetic lethality in a BRCA-deficient context, however, their efficacy is frequently hampered by intrinsic or acquired resistance mechanisms involving restoration of the HR. In that regard, the role of some CDKs proven to regulate key HR actors was of interest to us.We aim at understanding the rewiring pathways determining resistance to PARPi in BRCA-deficient cancers and assessing the role of transcriptional regulating CDKs such as CDK7, CDK9 or CDK12 in the transcriptional regulation of key HR genes. Our ultimate goal is to determine whether and which CDK inhibitors could be effective approaches to repress HR gene expression and induce pharmacological HR-deficiency. As such, these CDK-inhibitors could be molecules of choice allowing sensitization of tumors that would otherwise respond poorly to DNA damaging treatment. With this purpose, we use in vitro and in vivo (PDX) models of TNBC and study the attenuation of HR response in tumor cells and PDX models treated with CDK-inhibitors. Our final aim is to determine the most efficient combination CDK-I + PARP-I. Our HR read outs are RAD51 and BRCA1 foci formation upon PARP-I treatment. We also measure the modification of RNA and protein expression levels induced by CDK-I treatment on a series of diagnostic HR genes (BRCA2, PALB2, ATR, FAND2), as a measure of HR repression. We will present data comparing the relative efficiency of 3 CDK-I, dinaciclib, NVP-2 and SR-4835, which have different specificities and inhibit different CDKs with variable efficacy.
利用CDK抑制策略研究三阴性乳腺癌DNA修复缺陷
三阴性乳腺癌(TNBC)占乳腺癌的15%,是一种侵袭性乳腺癌亚型,转移概率高,治疗选择有限。值得注意的是,brca缺陷发生在25%的tnbc中,并导致同源重组(HR)修复缺陷。有趣的是,PARP抑制剂(PARPi)在brca缺乏的情况下显示出合成致死性,然而,它们的效力经常受到涉及HR恢复的内在或获得性耐药机制的阻碍。在这方面,我们对一些CDKs的作用感兴趣,这些CDKs被证明可以调节关键的人力资源参与者。我们的目标是了解brca缺陷癌症中决定PARPi耐药性的重布线途径,并评估转录调节cdk(如CDK7、CDK9或CDK12)在关键HR基因转录调节中的作用。我们的最终目标是确定CDK抑制剂是否以及哪些可以有效抑制HR基因表达并诱导药理学上的HR缺乏。因此,这些cdk抑制剂可能是使肿瘤敏感化的首选分子,否则这些肿瘤对DNA损伤治疗反应不佳。为此,我们使用TNBC的体外和体内(PDX)模型,研究cdk抑制剂治疗肿瘤细胞和PDX模型中HR反应的衰减。我们的最终目标是确定CDK-I + PARP-I的最有效组合。我们的HR读数是PARP-I治疗后RAD51和BRCA1灶的形成。我们还测量了CDK-I治疗对一系列HR诊断基因(BRCA2, PALB2, ATR, FAND2)诱导的RNA和蛋白质表达水平的修饰,作为HR抑制的测量。我们将提供数据比较3种CDK-I、dinaciclib、NVP-2和SR-4835的相对效率,它们具有不同的特异性,抑制不同CDKs的效果也不同。
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