Functional genomic screen in mesothelioma reveals that loss of function of BRCA1-associated-protein-1 induces chemoresistance to ribonucleotide reductase inhibition

Okonska, Agata; Bühler, Saskja; Rao, Vasundhara; Ronner, Manuel; Blijlevens, Maxime; van der Meulen-Muileman, Ida H; de Menezes, Renée X; Wipplinger, Martin; Oehl, Kathrin; Smit, Egbert F; Weder, Walter; Stahel, Rolf A; Penengo, Lorenza; van Beusechem, Victor W; Felley-Bosco, Emanuela

doi:10.1158/1535-7163.MCT-19-0356

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Okonska, A., Bühler, S., Rao, V., Ronner, M., Blijlevens, M., van der Meulen-Muileman, I. H., de Menezes, R. X., Wipplinger, M., Oehl, K., Smit, E. F., Weder, W., Stahel, R. A., Penengo, L., van Beusechem, V. W., & Felley-Bosco, E. (2020). Functional genomic screen in mesothelioma reveals that loss of function of BRCA1-associated-protein-1 induces chemoresistance to ribonucleotide reductase inhibition. Molecular Cancer Therapeutics, 19(2), 552–563. https://doi.org/10.1158/1535-7163.MCT-19-0356

Abstract

Loss of function of BRCA1 associated protein 1 (BAP1) is observed in about 50% of malignant pleural mesothelioma (MPM) cases. The aim of this study was to investigate whether this aspect could be exploited for targeted therapy. A genetically engineered model was established expressing either functional or non-functional BAP1 and whole-genome siRNA synthetic lethality screens were performed assessing differentially impaired survival between the two cell lines. The whole-genome siRNA screen unexpectedly revealed 11 hits (FDR<0.05) that