Repurposing the Neurokinin-1 receptor antagonist Aprepitant to eradicate relapsed/refractory acute lymphoblastic leukemia via mitochondria-driven necroptosis

The prognosis for relapsed/refractory acute lymphoblastic leukemia (R/R ALL) remains dismal due to intrinsic and acquired chemoresistance, highlighting an urgent need for novel therapeutic strategies. The neurokinin-1 receptor (NK-1R) represents an emerging oncological target, yet its role and therapeutic potential in ALL are incompletely understood. Here, we identify the NK-1R as a robust therapeutic target that is significantly overexpressed in both primary and R/R ALL. The FDA-approved NK-1R antagonist Aprepitant potently inhibited the proliferation of ALL cells and overcame resistance to chemotherapeutic drugs in both patient-derived samples and doxorubicin-resistant cell lines. Mechanistically, Aprepitant triggered a novel mitochondria-driven necroptotic pathway, distinct from the apoptosis induced by NK-1R blockade in other cancers we previously reported [5,6]. This pathway is initiated by endoplasmic reticulum (ER) calcium release and ER stress, leading to mitochondrial calcium overload, reactive oxygen species (ROS) burst, and subsequent mitochondrial fission, which ultimately activates the phosphorylation of the core necroptotic effectors RIP1, RIP3, and MLKL. Pharmacological inhibition or genetic knockdown of key regulators of necroptosis, ER stress, or mitochondrial ROS significantly attenuated Aprepitant-induced cell death. Importantly, Aprepitant exhibited significant in vivo anti-leukemic efficacy in a xenograft mouse model. Our findings not only elucidate a unique, mitochondria-mediated necroptotic mechanism engaged by NK-1R inhibition but also provide a compelling rationale for the immediate clinical repurposing of Aprepitant as a targeted therapy for R/R ALL.