Tags

Type your tag names separated by a space and hit enter

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

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 were more cytotoxic to BAP1-proficient cells. Two actionable targets, ribonucleotide reductase (RNR) catalytic subunit M1 (RRM1) and RNR regulatory subunit M2 (RRM2), were validated. In line with the screen results, primary mesothelioma (BAP1+/-) overexpressing BAP1 C91A (catalytically dead mutant) were more resistant to RNR inhibition, while BAP1 knockdown in the BAP1-proficient cell lines rescued the cells from their vulnerability to RNR depletion. Gemcitabine and hydroxyurea were more cytotoxic in BAP1-proficient cell line-derived spheroids compared to BAP1-deficient. Upregulation of RRM2 upon gemcitabine and hydroxyurea treatment was more profound in BAP1 mut/del cell lines. Increased lethality mediated by RNR inhibition was observed in NCI-H2452 cells reconstituted with BAP1-WT but not with BAP1 C91A. Upregulation of RRM2 in NCI-H2452-BAP1 WT spheroids was modest compared to control or C91A mutant. Together, we found that BAP1 is involved in the regulation of RNR levels during replication stress. Our observations reveal a potential clinical application where BAP1 status could serve as predictive or stratification biomarker for RNR inhibition-based therapy in MPM.

Authors+Show Affiliations

Laboratory of Molecular Oncology, University Hospital Zürich.Laboratory of Molecular Oncology, University Hospital Zürich.Laboratory of Molecular Oncology, University Hospital Zürich.Laboratory of Molecular Oncology, University Hospital Zürich.Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam.Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam.Epidemiology and Biostatistics, Amsterdam UMC, location VUmc.Laboratory of Molecular Oncology, University Hospital Zürich.Institute of Pathology and Molecular Pathology, University Hospital Zürich.Department of Thoracic Surgery, Netherlands Cancer Institute.Division of Thoracic Surgery, University Hospital Zürich.Comprehensive Cancer Center, University Hospital Zürich.Institute of Molecular Cancer Research, University of Zurich.Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam.Laboratory of Molecular Oncology, University Hospital Zürich emanuela.felley-bosco@usz.ch.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31619462

Citation

Okonska, Agata, et al. "Functional Genomic Screen in Mesothelioma Reveals That Loss of Function of BRCA1-associated-protein-1 Induces Chemoresistance to Ribonucleotide Reductase Inhibition." Molecular Cancer Therapeutics, 2019.
Okonska A, Bühler S, Rao V, et al. Functional genomic screen in mesothelioma reveals that loss of function of BRCA1-associated-protein-1 induces chemoresistance to ribonucleotide reductase inhibition. Mol Cancer Ther. 2019.
Okonska, A., Bühler, S., Rao, V., Ronner, M., Blijlevens, M., van der Meulen-Muileman, I. H., ... Felley-Bosco, E. (2019). Functional genomic screen in mesothelioma reveals that loss of function of BRCA1-associated-protein-1 induces chemoresistance to ribonucleotide reductase inhibition. Molecular Cancer Therapeutics, doi:10.1158/1535-7163.MCT-19-0356.
Okonska A, et al. Functional Genomic Screen in Mesothelioma Reveals That Loss of Function of BRCA1-associated-protein-1 Induces Chemoresistance to Ribonucleotide Reductase Inhibition. Mol Cancer Ther. 2019 Oct 16; PubMed PMID: 31619462.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Functional genomic screen in mesothelioma reveals that loss of function of BRCA1-associated-protein-1 induces chemoresistance to ribonucleotide reductase inhibition. AU - Okonska,Agata, AU - Bühler,Saskja, AU - Rao,Vasundhara, AU - Ronner,Manuel, AU - Blijlevens,Maxime, AU - van der Meulen-Muileman,Ida H, AU - de Menezes,Renée X, AU - Wipplinger,Martin, AU - Oehl,Kathrin, AU - Smit,Egbert F, AU - Weder,Walter, AU - Stahel,Rolf A, AU - Penengo,Lorenza, AU - van Beusechem,Victor W, AU - Felley-Bosco,Emanuela, Y1 - 2019/10/16/ PY - 2019/10/10/accepted PY - 2019/04/02/received PY - 2019/09/06/revised PY - 2019/10/18/entrez PY - 2019/10/18/pubmed PY - 2019/10/18/medline JF - Molecular cancer therapeutics JO - Mol. Cancer Ther. N2 - 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 were more cytotoxic to BAP1-proficient cells. Two actionable targets, ribonucleotide reductase (RNR) catalytic subunit M1 (RRM1) and RNR regulatory subunit M2 (RRM2), were validated. In line with the screen results, primary mesothelioma (BAP1+/-) overexpressing BAP1 C91A (catalytically dead mutant) were more resistant to RNR inhibition, while BAP1 knockdown in the BAP1-proficient cell lines rescued the cells from their vulnerability to RNR depletion. Gemcitabine and hydroxyurea were more cytotoxic in BAP1-proficient cell line-derived spheroids compared to BAP1-deficient. Upregulation of RRM2 upon gemcitabine and hydroxyurea treatment was more profound in BAP1 mut/del cell lines. Increased lethality mediated by RNR inhibition was observed in NCI-H2452 cells reconstituted with BAP1-WT but not with BAP1 C91A. Upregulation of RRM2 in NCI-H2452-BAP1 WT spheroids was modest compared to control or C91A mutant. Together, we found that BAP1 is involved in the regulation of RNR levels during replication stress. Our observations reveal a potential clinical application where BAP1 status could serve as predictive or stratification biomarker for RNR inhibition-based therapy in MPM. SN - 1538-8514 UR - https://www.unboundmedicine.com/medline/citation/31619462/Functional_genomic_screen_in_mesothelioma_reveals_that_loss_of_function_of_BRCA1-associated-protein-1_induces_chemoresistance_to_ribonucleotide_reductase_inhibition L2 - http://mct.aacrjournals.org/cgi/pmidlookup?view=long&amp;pmid=31619462 DB - PRIME DP - Unbound Medicine ER -