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Abstract Introduction: Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer, with limited targeted treatment options. TNBC patients can, however, benefit from targeted drugs known as Poly (ADP-Ribose) Polymerase inhibitors (PARPi). PARPi disrupt DNA repair pathways by targeting tumors with germline BRCA1/2 mutations (BRCA-MUT) via synthetic lethality and PARP-DNA trapping mechanisms. Only 15-20% of the TNBC patient population are BRCA-MUT and can thus benefit from PARPi. However, preclinical studies and clinical trials have suggested that PARPi can also be effective in BRCA1/2 wild-type (BRCA-WT) cancer cells that have genomic phenotypes similar to BRCA-MUT cells, a phenomenon known as BRCAness. Previously, we used whole transcriptome analysis in a panel of TNBC cell lines to identify a 63-gene signature for BRCAness. The 63-gene signature was shown to predict response to PARPi with an accuracy of 86% in patient-derived xenografts, and was present in 45% of TNBC patients. We hypothesize that targeting genes in this 63-gene signature can enhance the sensitivity of PARPi in BRCA-WT and BRCA-MUT TNBC cells. Our aim is to identify and target genes from this signature that are involved in DNA synthesis and repair pathways, to identify effective combination strategies with PARPi. Methods: Using a PARPi-resistant TNBC cell line, MDAMB231, we carried out an siRNA screen of six genes from the 63-gene signature (BARD1, BUB1, RRM2, FEN1, EXO1, and USP1), chosen based on DNA repair functions and small-molecule inhibitor availability. The gene knockdowns were combined with the application of a potent PARPi, talazoparib, to determine the impact on DNA damage and cell death in TNBC cell lines. We then focused on targeting FEN1 function with the inhibitor LNT1. Using the Chou Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4529.
Fyle et al. (2024) studied this question.