Alterations in <i>BAP1</i> Are Associated with Cisplatin Resistance through Inhibition of Apoptosis in Malignant Pleural Mesothelioma.

Abstract

The clinical standard treatment for patients with malignant pleural mesothelioma (MPM) includes a cisplatin-based chemotherapy, leading to reduction of tumor size in only a minority of patients. Predicting response to chemotherapy in patients with MPM by using a genetic marker would, therefore, enable patient stratification. In this retrospective biomarker study, eligible patients had resectable MPM, measurable disease, and available primary MPM tissue. All patients underwent first-line treatment with cisplatin and pemetrexed, followed by surgery. Thorough molecular analysis was performed (whole-exome and targeted deep sequencing, and copy-number analyses), and also mechanistic <i>in vitro</i> data (viability assays, Western blots, and immunoprecipitation) using mesothelioma cell lines with and without siRNA-mediated BRCA1-associated protein 1 (BAP1) knockdown were provided. In a training cohort of patients with MPM (<i>n</i> = 28), mutations or deletions of <i>BAP1</i> each predicted resistance to chemotherapy in patients with primary MPM. The negative predictive value of <i>BAP1</i> loss in patients with MPM was confirmed by amplicon sequencing and copy-number array technology in an independent test cohort (<i>n</i> = 39). Preliminary mechanistic studies using siRNA-based knockdown of BAP1 in MPM cell culture models along with immunoprecipitation assays confirmed chemoresistance <i>in vitro</i>, possibly through inhibition of apoptosis and transcriptional regulation of the BAP1/HCF1/E2F1 axis. Alterations in <i>BAP1</i> in MPM were a negative predictor for response to chemotherapy and could possibly be used as a companion biomarker for treatment decision.