Unesbulin overcomes Cisplatin resistance in pleural mesothelioma via induction of apotosis, aberrant tubulin polymerization and inactivation of the BMI1 oncogene

Background Resistance to the standard therapeutics Cisplatin/Pemetrexed is the major cause of death in pleural mesothelioma (PM). Unesbulin (PTC596) is an investigational small-molecule tubulin-binding agent that is currently been tested in clinical studies with advanced leiomyosarcoma patients. Unlike other tubulin-binding agents, Unesbulin is orally bioavailable and is not a P-glycoprotein substrate. We investigated the efficacy of Unesbulin to inhibit growth and viability of PM cells and its ability to sensitize towards Cisplatin/Pemetrexed.

Methods & Materials The effects of Unesbulin on PM cells were analyzed using assays monitoring viability, real-time cell death and tubulin polymerization, immunofluorescence and immunoblotting.

Results Unesbulin was toxic in all six PM cell lines and primary cells of three PM patients at sub-micromolar concentrations, in particular in PM cells resistant to Cisplatin and Pemetrexed, while normal fibroblasts were only modestly affected. Mechanistically, Unesbulin inactivated the oncogene BMI and targeted tubulin polymerization via direct interaction with tubulin. Formation of aberrant tubulin fibers caused abnormal spindle morphology, mitotic arrest and apoptosis. Unesbulin sensitized Cisplatin/Pemetrexed resistant PM cell lines and primary cells towards Cisplatin and Cisplatin/Pemetrexed induced cell killing.

Conclusion Unesbulin induces a potent anti-tumor effect by disrupting microtubule assembly and inactivating BMI1, with only modest effects on non-malignant cells. Unesbulin sensitizes PM cells towards Cisplatin/Pemetrexed, thus revealing a promising therapeutic strategy to overcome PM drug resistance.

Publikationsverlauf

Artikel online veröffentlicht:
25. August 2025