Birinapant (TL32711) Improves Responses to GEM/AZD7762 Combination Therapy in Triple-negative Breast Cancer Cell Lines

Background: Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer currently lacking targeted therapies. Our previous work demonstrated a therapeutic synergism with gemcitabine (GEM) and the CHK1 inhibitor (AZD7762) combination treatment in a TNBC cell line. We hypothesized that the response to this combination therapy would differ among heterogeneous TNBC patients and that addition of a SMAC mimetic (TL32711) could improve efficacy. Materials and Methods: Therapeutic responses to GEM, GEM/AZD7762, and GEM/AZD7762/TL32711 combinations were investigated by XTT assays and western blotting of cell cycle and apoptosis-related proteins in ten TNBC cell lines. Results: TNBC cell lines harboring low levels of endogenous CHK1, cIAP1 and cIAP2 were responsive to GEM alone, whereas cell lines demonstrating a minimal increase in phospho-S345 CHK1 after treatment were responsive to GEM/AZD7762 or GEM/AZD7762/TL32711 combination. Conclusion: The response of TNBC cells to particular therapies varies and will require development of predictive biomarkers.

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