Is DNA repair a potential target for effective therapies against malignant mesothelioma?

Our plain-English summary of Is DNA repair a potential target for effective therapies against malignant mesothelioma?, by I. Fuso Nerini, E. Roca, L. Mannarino, et al (Cancer Treatment Reviews, 2020).

The study

• Authors: I. Fuso Nerini, E. Roca, L. Mannarino, F. Grosso, R. Frapolli, M. D'Incalci
• Journal: Cancer Treatment Reviews
• Published: 2020;90:102101
• Type of article: Review
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is a rare malignancy mainly caused by asbestos exposure. Germinal and acquired mutations in genes of DNA repair pathways, in particular of homologous recombination repair, are frequent in MPM. Here we overview the available experimental data suggesting that an impaired DNA repair system affects MPM pathogenesis by leaving lesions through the genome unresolved. DNA repair defects represent a vulnerability of MPM, and it seems plausible to propose that leveraging these deficiencies could have therapeutic potential for patients with MPM, for whom there is an urgent need of more effective therapies.

Copyright © 2020. Published by Elsevier Ltd.

In plain English

This article was a review, not a new study of patients. The authors gathered published laboratory, animal and clinical research on whether faults in the cell's DNA repair systems contribute to malignant pleural mesothelioma, which the article describes as mainly caused by asbestos exposure. They also asked whether such faults could be targeted by treatment. In the authors' own analysis of public tumor data, more than 60% of 82 mesothelioma samples carried at least one change in a DNA damage response gene. Studies the authors cited reported three things. About 50% of patients in one cohort had defects in a repair pathway called homologous recombination. Changes in the BAP1 gene were seen in 30–60% of patients' tumors. Mice with one faulty Bap1 copy often developed mesothelioma after relatively low asbestos doses. Early trial reports were mixed: olaparib showed limited effect in 23 patients, while rucaparib met its 12-week disease control goal in 26 patients. The authors concluded there was a robust rationale for clinical studies. They added that the data were not yet consistent or clear enough to point toward clinical use.

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: Narrative review of published experimental and clinical studies on DNA repair in malignant pleural mesothelioma, plus the authors' own look at publicly available tumor genome data (The Cancer Genome Atlas)
• Who was studied: Published laboratory (cell line), animal (mouse) and human studies, including early clinical trials, on mesothelioma and DNA repair. The authors' own analysis used Cancer Genome Atlas data on 82 mesothelioma samples.
• Exposure: The review concerns inherited and acquired defects in DNA repair genes (for example BAP1, BRCA2, XRCC1, ERCC1) and drugs targeting DNA repair. Asbestos is described as the main cause of the disease, but no fiber types or doses were studied by the authors.
• Main results:
  • In the authors' analysis of Cancer Genome Atlas data, more than 60% of the 82 mesothelioma samples had at least one somatic variant in at least one DNA damage response gene (including BAP1).
  • A cited study (Panou et al.) reported that approximately 50% of its cohort of mesothelioma patients had defects in the homologous recombination repair pathway, either inherited or acquired.
  • Cited studies observed somatic (tumor) changes in BAP1 in 30–60% of patients with malignant pleural mesothelioma.
  • In cited mouse studies, mesothelioma incidence was high in mice with one inactivated Bap1 copy when they were exposed to relatively low doses of asbestos.
  • Cited studies of large biopsy series suggested that mismatch repair deficiency is rare in mesothelioma, occurring in not more than 2.5% of cases.
  • Cited studies reported that mesothelioma patients with inherited mutations in BAP1, BRCA2, MLH1, MRE11A or PALB2 had better overall survival after standard chemotherapy than patients without these variants.
  • In cited cell-line studies, PARP inhibitor drugs killed multiple mesothelioma cell lines, but this effect was mostly independent of BAP1 mutation status.
  • Preliminary results of a phase II olaparib trial, after 23 patients were recruited, indicated limited antitumor efficacy in mesothelioma patients, including those with BAP1 mutations.
  • In the rucaparib arm of the MiST trial, preliminary results after recruitment of 26 patients were reported as meeting the primary endpoint of disease control rate at 12 weeks, with manageable toxicity.
• The authors' conclusion: The authors proposed that DNA repair defects play a central role in how mesothelioma develops. They concluded that there is a robust rationale for clinical studies of PARP inhibitors and other DNA repair-targeting drugs in patients whose tumors have been characterized for DNA damage response defects.
• Limitations the authors state:
  • The authors stated that, overall, the data on DNA repair defects were not consistent or clear enough to suggest paths toward clinical application.
  • The authors noted that studies linking tumor molecular profiles to clinical outcome often lacked statistical significance because of small sample numbers.
  • The authors noted a lack of solid preclinical data supporting PARP inhibitors in mesothelioma.
  • The authors noted that few studies had been performed on clinical specimens.

Topics

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

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Pleural Mesothelioma, Asbestos Exposure.

Related studies

• 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)
• Repositioning PARP inhibitors in the treatment of thoracic malignancies — F. Passiglia, M.L. Reale, et al. (2021)
• Are glutathione S transferases involved in DNA damage signalling? Interactions with DNA damage and repair revealed from molecular epidemiology studies — M. Dusinska, M. Staruchova, et al. (2012)
• DNA repair systems in malignant mesothelioma — D. Toumpanakis, S.E. Theocharis (2011)
• DNA repair polymorphisms and treatment outcomes of patients with malignant mesothelioma treated with gemcitabine-platinum combination chemotherapy — N. Erčulj, V. Kovač, et al. (2012)
• Germline mutations in DNA repair genes predispose asbestos-exposed patients to malignant pleural mesothelioma — M. Betti, E. Casalone, et al. (2017)

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