DNA repair and damage pathways in mesothelioma development and therapy

Our plain-English summary of DNA repair and damage pathways in mesothelioma development and therapy, by F. Malakoti, N. Targhazeh, E. Abadifard, et al (Cancer Cell International, 2022).

The study

• Authors: F. Malakoti, N. Targhazeh, E. Abadifard, R. Zarezadeh, S. Samemaleki, Z. Asemi, S. Younesi, R. Mohammadnejad, S. Hadi Hossini, A. Karimian, F. Alemi, B. Yousefi
• Journal: Cancer Cell International
• Published: 2022;22(1):176
• Type of article: Review
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MMe) is an aggressive neoplasm that occurs through the transformation of mesothelial cells. Asbestos exposure is the main risk factor for MMe carcinogenesis. Other important etiologies for MMe development include DNA damage, over-activation of survival signaling pathways, and failure of DNA damage response (DDR). In this review article, first, we will describe the most important signaling pathways that contribute to MMe development and their interaction with DDR. Then, the contribution of DDR failure in MMe progression will be discussed. Finally, we will review the latest MMe therapeutic strategies that target the DDR pathway.

© 2022. The Author(s).

In plain English

This article was a review: the authors summarized published research and created no new data. It described how several cell signaling pathways (Hedgehog, PI3K/AKT/mTOR, MAPK and calcium) and failures of DNA repair are involved in malignant mesothelioma, and reviewed treatments aimed at DNA repair. The authors described asbestos fibers as the main cause of mesothelioma, producing reactive molecules that damage DNA; no specific fiber types were discussed. Among the studies reviewed, a 2018 study reported that 83% of germline mutations in mesothelioma cases were in DNA damage response genes, and several studies reported BAP1 gene mutations in 30–60% of cases. The review also covered laboratory research on PARP inhibitor drugs and research suggesting that pleural mesothelioma patients with BAP1 deficiency may respond better to immune checkpoint inhibitor drugs. The authors concluded that targeting DNA repair could be a promising approach, but that there is a long way to go and further research is needed to prove it works.

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 research; no new data were created or analyzed
• Who was studied: No participants of the authors' own. The review drew on published studies of malignant mesothelioma, both pleural and peritoneal, including cell-line, animal and patient studies.
• Exposure: Asbestos is described as the main cause of malignant mesothelioma, acting through reactive oxygen and nitrogen species that damage DNA. No specific fiber types, products, jobs or doses are discussed.
• Main results:
  • Cited 2018 study (not the authors' own): 83% of germline mutations in mesothelioma cases were in DNA damage response genes, and 50% were in the homologous recombination pathway.
  • Summarizing several cited studies, 30–60% of malignant mesothelioma cases show BAP1 gene mutations, including point mutations and exon deletions.
  • Cited studies reported that overexpression of Hedgehog pathway target genes in malignant pleural mesothelioma is associated with the worst clinical outcome.
  • From the reviewed literature, the XRCC1-399Q gene variant is correlated with malignant pleural mesothelioma only in combination with asbestos exposure.
  • Cited laboratory studies reported that cells defective in homologous recombination repair are 100 times more sensitive to the drug trabectedin.
  • Cited recent research suggests that malignant pleural mesothelioma patients with BAP1 deficiency may form a distinct subset with increased sensitivity to immune checkpoint inhibitor therapies.
• The authors' conclusion: The authors concluded that regulating the DNA damage response could be a promising approach to stop mesothelioma cell progression. In their view, there is a long way to go, and further investigations are required to prove that this strategy works.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Malignant Mesothelioma, Neoplasm, Mesothelial Cells, Asbestos Exposure, Carcinogenesis.

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• Novel Germline Mutations in DNA Damage Repair in Patients with Malignant Pleural Mesotheliomas — R. Guo, M. DuBoff, et al. (2020)
• Screening of Pleural Mesotheliomas for DNA-damage Repair Players by Digital Gene Expression Analysis Can Enhance Clinical Management of Patients Receiving Platin-Based Chemotherapy — R.F. Walter, C. Vollbrecht, et al. (2016)
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• Asbestos induces mitochondrial DNA damage and dysfunction linked to the development of apoptosis — A. Shukla, M. Jung, et al. (2003)

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