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Exploiting DNA Repair Defect in Triple Negative Brest Cancer Using CDK Inhibition Strategy
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1  Genetic and phenotypic plasticity of cancer" team Institut de Recherche en Cancérologie de Montpellier (IRCM)


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.

Keywords: triple negativo breast cancer, targeted therapy, BRCAness