BAP1 Status Determines the Sensitivity of Malignant Mesothelioma Cells to Gemcitabine Treatment

Abstract

Malignant mesothelioma (MMe) is a cancer with poor prognosis and resistance to standard treatments. Recent reports have highlighted the role of the BRCA1 associated protein 1 gene (BAP1) in the development of MMe. In this study, the chemosensitivity of human mesothelioma cell lines carrying BAP1 wild-type (WT), mutant and silenced was analysed. The BAP1 mutant cells were significantly less sensitive than BAP1 WT cell lines to the clinically relevant drug gemcitabine. Silencing of BAP1 significantly increased resistance of MMe cells to gemcitabine. Cell cycle analysis suggested that gemcitabine induced Sub-G1 phase accumulation of the BAP1 WT cells and increased in the S-phase in both BAP1 WT and mutant cells. Analysis of the role of BAP1 in apoptosis suggested that gemcitabine induced early apoptosis in both BAP1 WT and BAP1 mutant cells but with a much higher degree in the WT cells. Effects on the population of cells in late apoptosis, which can mark necrosis and necroptosis, could not be seen in the mutant cells, highlighting the possibility that BAP1 plays a role in several types of cell death. Significantly decreased DNA damage in the form of double-strand breaks was observed in gemcitabine-treated BAP1 mutant cells, compared to BAP1 WT cells under the same conditions. After BAP1 silencing, a significant decrease in DNA damage in the form of double-strand breaks was observed compared to cells transfected with scramble siRNA. Taken together, the results presented in this manuscript shed light on the role of BAP1 in the response of MMe cells to gemcitabine treatment and in particular in the control of the DNA damage response, therefore providing a potential route for more efficient MMe therapy.

Emerging Treatments for Malignant Pleural Mesothelioma: Where Are We Heading?

“…This is consistent with what already observed in ovarian and breast cancer patients with inherited mutations in BRCA1 and BRCA2 (55)(56)(57)(58). Conversely, BAP1 mutant mesothelioma cell lines resulted significantly less sensitive than BAP1 wild type cells to gemcitabine (59). In addition, the role of somatic BAP1 expression in MPM patients receiving chemotherapy still represents a matter of debate, with retrospective studies showing contradictory evidences (60,61).…”

Mesothelioma: Scientific clues for prevention, diagnosis, and therapy

“…These data indicate that BAP1 regulates RRM2 levels during replication stress and that patients could be stratified for gemcitabine treatment, depending on BAP1 status. In a parallel study, Mutti’s team demonstrated that mesothelioma cells with functional BAP1 were more sensitive to gemcitabine treatment compared with cells bearing mutated and nonfunctional BAP1 . Together, these independent studies indicate that it may be possible to identify those patients with mesothelioma—and possibly patients with any cancer—who are more likely to respond to gemcitabine based on BAP1 status.…”

Malignant Pleural Mesothelioma: State-of-the-Art on Current Therapies and Promises for the Future

“…RT is used as an adjuvant or neoadjuvant treatment in MPM, mainly in a palliative setting (8)(9)(10). As standard practice, patients undergoing an EPP receive adjuvant conventionally fractionated RT (50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60) in the ipsilateral hemithorax area (18,19). In node-negative MPM patients, neoadjuvant therapy, based on intensity-modulated RT (IMRT) consisting of a fractionated irradiation of 5-6 Gy, is delivered before EPP (20)(21)(22).…”