A Dual-Purpose Approach for an Anti-Emetic NK1R Antagonist as a Chemosensitizer and Cardioprotectant in a Preclinical Model of Triple-Negative Breast Cancer.

Doxorubicin (Dox) is considered one of the most effective treatments for triple-negative breast cancer (TNBC); however, it can cause limited efficacy, recurrence/chemoresistance, and cardiotoxicity. Using a murine preclinical MDA-MB-231 TNBC model, we determined that targeting the substance P/neurokinin-1 receptor signaling axis can increase efficacy of the standard-of-care treatment currently used for TNBC, i.e., doxorubicin (Dox), while also attenuating Dox-induced, cardiotoxicity in TNBC. The in vivo studies outlined in this manuscript validate aprepitant (AP), a neurokinin-1 receptor antagonist, as a safe, dual-purpose chemosensitizer and cardioprotectant. These studies provide preclinical evidence supporting further evaluation of a continuous daily AP regimen in TNBC models in combination with Dox, laying the groundwork for future investigations into its safety, dosing, and potential clinical application. Because AP is already FDA-approved for single-dose anti-emetic use, repurposing it for chronic administration offers a rapid path to clinical translation, with the potential to redefine chemotherapy paradigms and tangibly improve survival and quality of life in TNBC.