Alterations in BAP1 Are Associated with Cisplatin Resistance through Inhibition of Apoptosis in Malignant Pleural Mesothelioma

Abstract

Statement of Translational RelevanceMalignant Pleural Mesothelioma (MPM) is a rare, but fatal lung cancer. Due to the lack of many alternative treatment options, standard clinical therapy regimens include a platinum based therapy in combination with an antifolate. However, chemotherapy only shows effectiveness in about a third of all MPM patients, exposing two thirds of them to unnecessary and mostly severe side effects. In our project, we screened a cohort of 67 MPM patients undergoing similar cisplatin-based treatment for a genetic marker predictive of response to chemotherapy and found that alterations in BAP1 were a negative predictor of MPM outcome. Using different MPM cell lines, we demonstrated that the absence of BAP1 in vitro is causative for cisplatin resistance.We, therefore, suggested that BAP1 mutational status could be used for patient stratification before chemotherapeutic treatment. In view of the recent FDA-approval of ipilimumab plus nivolumab as first-line treatment for adults with unresectable MPM, neoadjuvant chemotherapy regimens for resectable MPM patients are to be discussed in case of BAP1 alterations.

Double-Stranded RNA Structural Elements Holding the Key to Translational Regulation in Cancer: The Case of Editing in RNA-Binding Motif Protein 8A

“…RBM8A protein is heterogeneously expressed in mesothelioma cell lines ( Figure 1 A), and the average levels are 4-fold higher in mesothelioma cell lines ( n = 14) when compared to normal mesothelial cells ( n = 5) ( Figure 1 A,B; p < 0.05). The SV40-immortalized Met5A line has intermediate RBM8A expression and was not included in the normal mesothelial cell group because it bears genetic mutations [ 31 ] and has a generally altered phenotype [ 32 ]. Data mining from (accessed on 28 April 2020) [ 33 ] revealed a weak (r < 0.7) although significant correlation between RBM8A mRNA and protein in cancer cells ( Supplementary Figure S1A ), and we observed similar results in our collection ( Supplementary Figure S1B ), indicating the involvement of post-transcriptional processes in regulating protein levels.…”

Malignant pleural mesothelioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up☆

“…Preclinical evidence and some series suggest that sensitivity to chemotherapeutic agents may be BAP1-driven and this has been observed also in MPM patients. [66,67] BAP1 loss has been evaluated as a possible biomarker of poly(ADP-ribose) polymerase (PARP) inhibitor efficacy. In a phase II trial of rucaparib in BAP1-or BRCA1-deficient patients (MiST1) rucaparib met the primary endpoint of disease control at 12 weeks (58%) [68] Other alterations that may be potentially actionable in MPM include…”

Advances in Immunotherapy of Malignant Pleural Mesothelioma

“…As confirmed in that article, BAP1 loss resulted in cisplatin resistance in vitro, which was mostly related to the decreased apoptosis. 43 In vivo and in vitro experiments, the BAP1 gene mutation MPM cells were resistant to the tumor EZH2 (enhancer of zeste homolog 2) is sensitive. Tazemetostat, the first EZH2 inhibitor in the world, has been approved by FDA for metastatic or advanced epithelioid sarcoma that is not suitable for surgical resection.…”

“…Loss of BAP1 leads to resistance to cisplatinin vitroand. [ 41 , 43 ] p14/ARF Pezzuto F 1. p14/ARF-positive epithelioid mesotheliomas may mark a more aggressive pathological phenotype (higher nuclear grade and PD-L1 expression) 2. p14/ARF-negative tumors seem to have an immune microenvironment less sensitive to immune checkpoint inhibitors36. [ 39 ] NF2 and Hippo-YAP Hmeljak J et al/Haitang Yang et al 1.…”