International Journal of Ratdiation Oncology, Biology, Physics 2019 November 28 [Link]
Jackson MR, Ashton M, Koessinger AL, Dick C, Verheij M, Chalmers AJ
The incidence of mesothelioma continues to rise and prognosis remains dismal due to resistance to conventional therapies and few novel treatment options. Failure to activate apoptotic cell death is a resistance mechanism that may be overcome by inhibition of anti-apoptotic Bcl-2 proteins using BH3-mimetic drugs. We investigated the role of anti-apoptotic proteins in the radioresistance of mesothelioma, identifying clinically-relevant targets for radiosensitization and evaluating the activity of BH3-mimetics alone and in combination with radiotherapy in pre-clinical models. Mesothelioma cell lines 211H, H2052 and H226 exposed to BH3-mimetics demonstrated Bcl-xL dependence that correlated with protein expression and was confirmed by genetic knockdown. The Bcl-xL inhibitor A1331852 exhibited cytotoxic (EC50 0.13-1.42 μmol/L) and radiosensitizing activities (sensitizer enhancement ratios 1.3-1.8). Cytotoxicity was associated with induction of mitochondrial outer membrane permeabilization and caspase-3/7 activation. Efficacy was maintained in a three-dimensional model in which combination therapy completely eradicated mesothelioma spheroids. Clinical applicability was confirmed by immunohistochemical analysis of Bcl-2 proteins in patient samples and radiosensitizing activity of A1331852 in primary patient-derived mesothelioma cells. Mesothelioma cells exhibit addiction to the anti-apoptotic protein Bcl-xL and their intrinsic radioresistance can be overcome by small molecule inhibition of this novel therapeutic target.