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.
