Dual action of pimozide through lysosome disruption and inhibition of STATs induces apoptosis in chronic lymphocytic leukemia (CLL).

Chronic lymphocytic leukemia (CLL) progression and therapeutic resistance are driven in large part by protective signals from the tumor microenvironment (TME), which includes T-cell-derived cytokines such as interleukin-4 (IL-4) that promote survival via signal transducer and activator of transcription (STAT) signaling and upregulation of antiapoptotic proteins such as the B-cell lymphoma 2 (BCL-2) family member myeloid cell leukemia 1 (MCL-1). Although the BCL-2 inhibitor venetoclax has demonstrated significant clinical efficacy, microenvironment-induced resistance, particularly by MCL-1 upregulation, remains a major limitation. Here, we identify the US Food and Drug Administration-approved antipsychotic drug pimozide as a dual-function agent that induces lysosome membrane permeabilization, leading to apoptosis in CLL cells through increased reactive oxygen species production. In addition, pimozide inhibited STAT5 phosphorylation, reduced IL-4-induced MCL-1 expression, and prevented IL-4/CD40L-mediated inhibition of apoptosis. Importantly, pimozide remains effective in inducing apoptosis in CLL cells from patients who have relapsed after therapy. Pimozide also synergizes with venetoclax to induce apoptosis in CLL cells even after IL-4/CD40L signaling. This suggests that dual targeting of lysosomal function and STAT signaling represents a promising therapeutic approach to improve venetoclax efficacy and overcome TME-mediated drug resistance in CLL.