Pitavastatin Shows Capable of Overcoming Chemotherapy Resistance in Triple-Neg Breast Cancer

Triple-negative breast cancer (TNBC) is one of the most aggressive types of breast cancer, lacking estrogen, progesterone and HER2 receptors, and therefore relies mainly on cytotoxic chemotherapy. Despite initial response, many patients experience rapid relapse caused by cancer stem cells that survive chemotherapy and seed metastasis.

Addressing this unmet need, researchers led by Professor Jae Hong Seo from Korea University discovered that pitavastatin, a widely prescribed cholesterol-lowering drug, can directly inhibit the anti-apoptotic protein Mcl-1, a key driver of survival, stemness and paclitaxel resistance in TNBC cells. This paper was published in Issue 14, Article 125, of Experimental Hematology & Oncology on October 22, 2025. “We are reporting this for the first time pitavastatin is a direct inhibitor of Mcl-1 and targets heterogeneity in TNBC cells through suppression of CSC-like properties, thereby preventing distant metastasis and reversing paclitaxel resistance.” Prof. Seo commented.

Using molecular docking and biophysical analyses, the team found that pitavastatin specifically binds to the BH3-binding groove of Mcl-1, disrupting its stability and causing mitochondrial dysfunction. This inhibition triggered a cascade of mitochondrial damage, leading to ROS generation, membrane disruption, cytochrome c release, and activation of cell death pathways. The drug effectively eliminated populations of cancer stem cells, reduced ALDH1 activity, suppressed CD44^high/CD24^low and CD24^high/CD49^high subpopulations and abruptly inhibited mammosphere formation. These effects were extended to patient-derived TNBC organoids, where pitavastatin significantly reduced organoid size and viability.

In CSC-derived allograft mouse models, pitavastatin significantly reduced tumor growth, angiogenesis, and lung metastasis without causing organ toxicity or causing significant body weight loss. Tumor sections showed a marked decrease in the proliferative index Ki-67 and increased apoptosis, along with suppressed angiogenesis. The drug also reduced circulating levels of MMP-2, MMP-9 and VEGF, key mediators of metastatic progression.

Paclitaxel-resistant TNBC cells, characterized by increased Mcl-1, MDR1/P-gp, JAK2-STAT3 signaling, and enhanced stemness, remained highly sensitive to pitavastatin. The drug decreased Mcl-1 and Bcl-2, decreased P-gp expression, suppressed STAT3 activation, and restored mitochondrial apoptosis. In resistant mammograms, pitavastatin eliminated the frequency of CSCs and prevented metastatic lung colonization in vivo. Combination therapy with paclitaxel and pitavastatin synergistically inhibited the growth of TNBC organoids, outperforming either drug alone. “Our results support pitavastatin as a promising drug repurposing candidate, particularly in TNBC characterized by high Mcl-1 expression and resistance to conventional chemotherapy.” Prof. Seo concluded.

The study highlights an exciting opportunity for drug repurposing: a well-established cardiovascular drug that exhibits potent antitumor and antimetastatic activity in a highly lethal subtype of breast cancer. With its known safety profile and mechanism-based targeting of Mcl-1, pitavastatin is emerging as a promising candidate for rapid clinical translation to improve outcomes for patients with chemotherapy-refractory TNBC.