The role of BCL-2 family proteins and therapeutic potential of BH3-mimetics in malignant pleural mesothelioma.

Abstract

With limited therapeutic changes in over a decade, a diagnosis of malignant pleural mesothelioma (MPM) is associated with poor survival and death within 12 months, making it one of the most lethal malignancies worldwide. Due to unregulated asbestos use in developing countries and through exposure associated with home renovations rather than industrial exposure, as was the case in the past, new cases of MPM are likely to present for decades to come. As MPM is largely driven by dysregulation of tumour suppressor genes, researchers have looked to other mechanisms of subverting tumour proliferation and spread. Over-expression of pro-survival BCL-2 family proteins impairs a cell's ability to undergo programmed cell death and BH3-mimetics which target these proteins, are a novel treatment option across haematological and some solid cancers, though have yet to be widely investigated in MPM. This review provides a succinct overview of MPM and its current treatment landscape. It summarises the role that BCL-2 family proteins play in tumorigenesis and the current therapeutic potential of BH3-mimetics across multiple cancer types. Finally, it discusses the role that BCL-2 family proteins play in MPM and the pre-clinical rationale for investigating BH3-mimetics as a therapeutic strategy. As a disease which lacks readily actionable oncogene driver mutations and displays only a modest benefit from immune checkpoint inhibition, novel therapeutic options are urgently needed for MPM. Hence, BH3-mimetics could be a promising treatment option for some solid cancers and potentially for MPM, where there is evidence supporting dependence on pro-survival BCL-2 proteins for MPM tumour cell survival.