Drug development against the hippo pathway in mesothelioma
Advances in the treatments for malignant pleural mesothelioma (MPM) have been disappointing until recently. Conventional cytotoxic drugs fail in MPM in part because they do not address the cancer stem cell population or stem cell pathways that drive tumor resistance and resurgence following treatment. The Hippo stem cell pathway regulates cell contact inhibition with tumor suppressor genes such as NF2 (Neurofibromatosis 2) upstream controlling YAP (Yes-associated protein 1) oncogenes. NF2 is mutated in 40–50% of all MPM and downstream YAP is constitutively active in greater than 70% of MPM, making the downstream YAP/TEAD (transcriptional enhancer associate domain) complex the ultimate target. Novel small molecule YAP inhibitors are showing promising results in preclinical studies and may prove to be effective chemotherapy drugs in MPM.