Alterations in Are Associated with Cisplatin Resistance through Inhibition of Apoptosis in Malignant Pleural Mesothelioma.

PURPOSE

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.

EXPERIMENTAL DESIGN

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 data (viability assays, Western blots, and immunoprecipitation) using mesothelioma cell lines with and without siRNA-mediated BRCA1-associated protein 1 (BAP1) knockdown were provided.

RESULTS

In a training cohort of patients with MPM ( = 28), mutations or deletions of each predicted resistance to chemotherapy in patients with primary MPM. The negative predictive value of loss in patients with MPM was confirmed by amplicon sequencing and copy-number array technology in an independent test cohort ( = 39). Preliminary mechanistic studies using siRNA-based knockdown of BAP1 in MPM cell culture models along with immunoprecipitation assays confirmed chemoresistance , possibly through inhibition of apoptosis and transcriptional regulation of the BAP1/HCF1/E2F1 axis.

CONCLUSIONS

Alterations in in MPM were a negative predictor for response to chemotherapy and could possibly be used as a companion biomarker for treatment decision.