Abstract P87: Combined therapy with CRIF1/CDK2 interface inhibitor and Taxol against Triple-Negative Breast Cancer

Abstract A chemotherapeutic agent, Paclitaxel (Taxol), remains the standard of care for the lethal triple-negative breast cancer (TNBC). However, over 50% of TNBC patients become resistant to chemotherapy typically after 6–10 months of treatment. To date, no solution is available. CR6-interacting factor 1 (CRIF1) is reported to act as a negative regulator of the cell cycle by interacting with cyclin-dependent kinase 2 (CDK2). In our study, two selective CRIF1–CDK2 interface inhibitors 4- (4-methylphenyl) -N-[3- (morpholin-4-yl) propylphthalazin-1-amine; bis (oxalic acid) and N-2- (benzylsulfanyl) ethyl-3-1- (3-nitrophenyl) methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydroquinazolin-3-ylpropanamide] were obtained by molecular modeling and docking and then used to investigate whether they could exert anti-proliferative activity on the TNBC cell lines. When combined with Taxol treatment, these two inhibitors are able to advance the cells from G0/G1 to S and G2/M phases, producing irreparable damage to the cells, which then undergo apoptosis. Moreover, they enhanced the reduction in cell proliferation induced by Taxol in TNBC cells, thereby improving sensitivity to Taxol in these cell lines. It is important that the inhibitors did not regulate the cell cycle in normal cells, indicating their high selectivity towards TNBC cells. The resistance to the anti-proliferative effects induced by Taxol can thus be significantly reduced by the combined treatment with selective CRIF1–CDK2 interface inhibitors, making a conceptual advance in the CDK-related cancer treatment. Animal assay will be carried out with improved interface inhibitors. Citation Format: Xiaoye Sang, Nassira Belmessabih, Ruixuan Wang, Preyesh Stephen 2024 Nov 13-15; Singapore. Philadelphia (PA): AACR; Cancer Res 2025;85 (15Suppl): Abstract nr P87.