Pitavastatin is a novel Mcl-1 inhibitor that overcomes paclitaxel resistance in triple-negative breast cancer

Background: Triple-negative breast cancer (TNBC) is notorious for its poor prognosis, high metastatic rates, and resistance to chemotherapy. We sought to investigate the anticancer effects of pitavastatin (PITA), a promising candidate for drug repurposing due to its potent inhibition of myeloid cell leukemia 1 (Mcl-1). Methods: The impact of PITA on TNBC cells was assessed in vitro by examining cell viability, apoptosis, mitochondrial function, and effects on cancer stem cell (CSC) properties. The interaction between PITA and Mcl-1 was explored using molecular docking simulations and surface plasmon resonance (SPR) assays. In vivo studies using CSC-enriched allografts and a paclitaxel-resistant metastatic model were conducted to understand translational relevance. Results: PITA’s direct inhibition of Mcl-1 enabled potent suppression of TNBC cells by selectively enhancing mitochondrial ROS production, reducing mitochondrial membrane potential, and depleting ATP content, triggering caspase-mediated apoptosis. PITA effectively targeted CSC-like subpopulations, marked by high ALDH1 activity and the CD44^high/CD24^low phenotype. By downregulating p-glycoprotein and Mcl-1/Bcl-2 signaling, PITA was also effective at counteracting paclitaxel resistance, and disrupted AKT/STAT3 survival pathways. PITA significantly inhibited the growth of TNBC patient-derived tumor organoids (PDTOs). Furthermore, its combination with paclitaxel exhibited a synergistic effect on TNBC organoid growth inhibition. In vivo, PITA exhibited potent anti-tumorigenic and anti-metastatic effects, significantly reducing tumor growth and lung metastasis in TNBC allograft models without overt toxicity. Conclusion: PITA’s inhibition of Mcl-1 represents a novel mechanism to address treatment-refractory metastatic TNBC. Further assessment of PITA’s therapeutic potential is warranted.