| الوصف: |
Triple-negative breast cancer (TNBC) is a difficult-to-treat breast cancer with limited therapeutic options. PARP inhibitors (PARPi) have emerged as a promising targeted therapeutic for TNBC patients with germline mutations in BRCA1/2, recently demonstrating inhibition of micrometastatic disease. However, studies have also suggested that PARPi may have efficacy in TNBC, regardless of BRCA mutation status. We have previously identified a 63-gene signature associated with the DNA damage response to PARPi, with an overall accuracy of 86% in a cohort of patient-derived xenografts and a predicted sensitivity to PARPi in 45% of untreated TNBC patients. Additionally, our 63-gene signature can be used to identify genes implicated in intrinsic resistance. Therefore, we hypothesize that genes from our 63-gene signature can be used to identify potential targets for combination therapies with PARPi. We selected six candidate genes from our 63-gene signature: BARD1, BUB1, FEN1, RRM2, EXO1, and USP1. For each of the selected genes, we performed siRNA knockdown experiments in MDAMB231, a TNBC cell line. Using flow cytometry, we found that talazoparib, a potent PARPi plus siBARD1, increased the proportion of cells in G2 phase, with 80% γ-H2AX-positive cells and 60% cleaved-caspase-3-positive cells. Interestingly, the DNA damage response was comparable to what was observed with the combination of talazoparib and carboplatin. Talazoparib + siBUB1 also induced DNA damage in 51% of cells (P Citation Format: Audrey Hubert, Alexia Cotte, Nelly Bechir, Takrima Haque, Saima N. Hassan. Identifying therapeutic targets in combination with PARP inhibitors using a 63-gene signature in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5342. |