The Association of BAP1 Loss-of-Function With the Defect in Homologous Recombination Repair and Sensitivity to PARP-Targeted Therapy

Our plain-English summary of The Association of BAP1 Loss-of-Function With the Defect in Homologous Recombination Repair and Sensitivity to PARP-Targeted Therapy, by H. Yang, D. Xu, Y. Gao, et al (Journal of Thoracic Oncology, 2020).

The study

• Authors: H. Yang, D. Xu, Y. Gao, R.A. Schmid, R.W. Peng
• Journal: Journal of Thoracic Oncology
• Published: 2020;15(6):e88-e90
• Type of article: Letter, Comment
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Summary of the article

In this letter to the editor, the authors responded to a recent study by Rathkey et al., which reported that the sensitivity of patient-derived malignant pleural mesothelioma (MPM) cells to PARP inhibitors did not depend on BAP1 mutational status. Earlier studies had linked BAP1 loss-of-function to defects in DNA double-strand break repair and to susceptibility to PARP-targeted therapy. To cross-validate the Rathkey findings, the authors reanalysed public data. They took drug screening results from the Genomics of Drug Sensitivity in Cancer database and genetic data from the Cancer Cell Line Encyclopedia for 20 MPM cell lines, 8 with and 12 without BAP1 mutations. They also used data on The Cancer Genome Atlas pleural mesothelioma cohort (n = 82) from cBioPortal. Some BAP1-altered lines (H2804, IST-MES1, H2795) and some wild-type lines (H2803, MSTO-211H) were particularly sensitive to PARP inhibitors (talazoparib, olaparib, veliparib, rucaparib), based on low IC50 z-scores. Other BAP1-mutant lines (H2452, H2731, H2722) were highly resistant. The authors proposed four possible explanations for this heterogeneity: co-occurring mutations, BAP1 splice isoforms, BAP1 functions beyond DNA repair, and cell lineage. They concluded that BAP1 mutational status in MPM does not seem to affect sensitivity to PARP-targeted therapy and that further studies are required.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.

In plain English

This letter to the editor concerns malignant pleural mesothelioma (MPM) and a gene called BAP1. Earlier studies had suggested that cancer cells lacking working BAP1 respond to drugs called PARP inhibitors. However, a recent study by Rathkey and colleagues found that MPM cell sensitivity to these drugs did not depend on BAP1 status. To cross-check, the authors reanalyzed public laboratory data on 20 MPM cell lines, 8 with and 12 without BAP1 mutations. These lines had been tested against the PARP inhibitors talazoparib, olaparib, veliparib and rucaparib. The particularly sensitive cell lines included some with BAP1 alterations and some without, while some BAP1-mutant lines were highly resistant. A figure based on a public set of 82 pleural mesothelioma tumors showed BAP1 alterations in 38%. The authors suggested possible explanations, such as other mutations occurring alongside BAP1 changes. They concluded that BAP1 mutational status in MPM does not seem to affect sensitivity to PARP-targeted therapy, and that further studies are needed. Drug sensitivity was measured in laboratory cell lines, not in treated patients, and the letter did not address asbestos exposure.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Letter to the editor reporting a reanalysis of publicly available laboratory drug-screening data (Genomics of Drug Sensitivity in Cancer) and tumor genetic data (The Cancer Genome Atlas, via cBioPortal), done to cross-check a prior study by Rathkey et al.
• Who was studied: 20 malignant pleural mesothelioma cell lines (8 with and 12 without BAP1 mutations) from a public database covering about 1000 human cancer cell lines; also genetic data from The Cancer Genome Atlas pleural mesothelioma cohort of 82 clinical cases
• Exposure: Not asbestos. The factors examined were BAP1 mutational status and laboratory sensitivity to PARP inhibitors (talazoparib, olaparib, veliparib, rucaparib).
• Main results:
  • Among the MPM cell lines, both BAP1-altered lines (H2804, IST-MES1, H2795) and BAP1 wild-type lines (H2803, MSTO-211H) were particularly sensitive to PARP inhibitors
  • Some BAP1-mutant MPM cell lines (H2452, H2731, H2722) were even more highly resistant to multiple PARP inhibitors
  • The authors interpreted the data as showing highly heterogeneous susceptibility of BAP1-mutant MPM cells to PARP inhibitors, supporting the work of Rathkey et al.
  • In The Cancer Genome Atlas pleural mesothelioma cohort (n = 82), the figure shows BAP1 genetic alterations in 38%
  • As one possible explanation for the varied responses, the authors proposed mutations co-occurring with BAP1 alterations
• The authors' conclusion: The authors concluded that BAP1 mutational status in MPM does not seem to affect sensitivity to PARP-targeted therapy, and that further studies are required.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: BAP1, Targeted Therapy, Pleural Mesothelioma.

Related studies

• Sensitivity of Mesothelioma Cells to PARP Inhibitors Is Not Dependent on BAP1 but Is Enhanced by Temozolomide in Cells With High-Schlafen 11 and Low-O6-methylguanine-DNA Methyltransferase Expression — D. Rathkey, M. Khanal, et al. (2020)
• Response to Letter to the Editor by Yang et al — R. Hassan, M. Sengupta, et al. (2020)
• Synthetic lethality in malignant pleural mesothelioma with PARP1 inhibition — G. Srinivasan, G.S. Sidhu, et al. (2017)
• A Novel BRCA1-Associated Protein-1 Isoform Affects Response of Mesothelioma Cells to Drugs Impairing BRCA1-Mediated DNA Repair — R. Parrotta, A. Okonska, et al. (2017)
• Chrysotile asbestos fibers mediate homologous recombination in Rat2 lambda fibroblasts: implications for carcinogenesis — K. Lezon-Geyda, C.M. Jaime, et al. (1996)
• Loss of BAP1 function leads to EZH2-dependent transformation — L.M. LaFave, W. Béguelin, et al. (2015)

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