Dual Targeting of Aurora-A and Bcl-xL Synergistically Reshapes the Immune Microenvironment and Induces Apoptosis in Breast Cancer.

Abstract

The Aurora-A kinase inhibitor MLN8237 has shown efficacy in clinical trials for advanced breast cancer; however, its use as a monotherapy is limited by significant side effects and modest efficacy. Therefore, combining MLN8237 with other agents at lower doses may provide a viable alternative. In this study, we evaluated the combination of MLN8237 with the BH3 mimetic ABT263 for the treatment of triple-negative breast cancer (TNBC). We found that this combination significantly suppressed tumor growth and metastasis in immunocompetent syngeneic mouse models, whereas its efficacy was attenuated in immunodeficient xenograft models. Mechanistic studies revealed that the combination enhanced anti-tumor immunity by increasing the presence of CD8⁺ T cells and NK cells, while reducing the number of immunosuppressive cells in the tumor microenvironment. This shift resulted in elevated levels of IFN-γ and granzyme B, which activated the extrinsic apoptotic pathways in cancer cells. Notably, the combination treatment did not affect tumor cell proliferation but promoted apoptosis with minimal toxicity. Furthermore, the synergistic effect of MLN8237 and ABT263 in inducing intrinsic apoptosis was primarily driven by the inhibition of the AKT-Mcl-1 and Bcl-xL survival pathways in cultured tumor cells. Together, these findings support the MLN8237-ABT263 combination as an effective treatment strategy for TNBC, promoting both immune-mediated extrinsic apoptosis and inactivation of Bcl-xL/Mcl-1-dependent intrinsic anti-apoptotic pathways.