Synthetic lethality in malignant pleural mesothelioma with PARP1 inhibition

Our plain-English summary of Synthetic lethality in malignant pleural mesothelioma with PARP1 inhibition, by G. Srinivasan, G.S. Sidhu, E.A. Williamson, et al (Cancer Chemotherapy and Pharmacology, 2017).

The study

• Authors: G. Srinivasan, G.S. Sidhu, E.A. Williamson, A.S. Jaiswal, N. Najmunnisa, K. Wilcoxen, D. Jones, T.J. George, R. Hromas
• Journal: Cancer Chemotherapy and Pharmacology
• Published: 2017;80(4):861-867
• Cited by: 50 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesotheliomas (MPM) are most often surgically unresectable, and they respond poorly to current chemotherapy and radiation therapy. Between 23 and 64% of malignant pleural mesothelioma have somatic inactivating mutations in the BAP1 gene. BAP1 is a homologous recombination (HR) DNA repair component found in the BRCA1/BARD1 complex. Similar to BRCA1/2 deficient cancers, mutation in the BAP1 gene leads to a deficient HR pathway and increases the reliance on other DNA repair pathways. We hypothesized that BAP1-mutant MPM would require PARP1 for survival, similar to the BRCA1/2 mutant breast and ovarian cancers. Therefore, we used the clinical PARP1 inhibitors niraparib and olaparib to assess whether they could induce synthetic lethality in MPM. Surprisingly, we found that all MPM cell lines examined, regardless of BAP1 status, were addicted to PARP1-mediated DNA repair for survival. We found that niraparib and olaparib exposure markedly decreased clonal survival in multiple MPM cell lines, with and without BAP1 mutations. This clonal cell death may be due to the extensive replication fork collapse and genomic instability that PARP1 inhibition induces in MPM cells. The requirement of MPM cells for PARP1 suggests that they may generally arise from defects in HR DNA repair. More importantly, these data demonstrate that the PARP1 inhibitors could be effective in the treatment of MPM, for which little effective therapy exists.

In plain English

This short communication reported laboratory experiments on mesothelioma cells grown in dishes. It did not involve patients, animals, or asbestos exposure. The authors tested two drugs that block a DNA repair protein called PARP1, niraparib and olaparib, on six malignant pleural mesothelioma (MPM) cell lines: four with mutations in the BAP1 gene and two without. Both drugs were reported to be significantly toxic to each cell line regardless of BAP1 status, with little difference in sensitivity to niraparib between the two groups. At 3 micromolar niraparib, colony survival of the cell lines averaged less than 10%. One BAP1-normal line, CRL-2081, was significantly less sensitive to olaparib than to niraparib. Further tests used one BAP1-mutant cell line, H2452. After niraparib, these cells showed a 3.5-fold decrease in BrdU foci, a marker of DNA replication restarting. Compared with control cells, they also showed a sevenfold increase in a DNA damage marker, threefold more micronuclei, twofold more nuclear bridging and ninefold more sister chromatid exchanges. The authors concluded that clinical trials of these drugs in MPM would be warranted. The study tested cells only, not people.

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: laboratory study of cultured cancer cell lines (short communication); no human participants or animals
• Who was studied: Six malignant pleural mesothelioma cell lines: four with BAP1 mutations (H-Meso01, H2452, H2461, H2731) and two with normal (wild-type) BAP1 (CRL-2081, H290)
• Exposure: The PARP1 inhibitor drugs niraparib and olaparib, mainly at 3 μM, with a range of niraparib doses in one cell line. Asbestos is mentioned only in the introduction and was not studied.
• Main results:
  • Niraparib and olaparib were significantly toxic to each of the MPM cell lines tested, whether or not the cells had BAP1 mutations
  • Little difference in sensitivity to niraparib was found between BAP1-mutant and BAP1 wild-type MPM cell lines
  • At 3 μM niraparib, clonal survival of the MPM cell lines averaged less than 10%
  • The BAP1 wild-type line CRL-2081 was significantly less sensitive to olaparib than to niraparib
  • In the BAP1-mutant line H2452, the IC50 of niraparib (the dose that halves colony formation) was 400 nM
  • BAP1-mutant MPM cells (H2452, printed as 'H2542' in this passage) treated with 3 μM niraparib for 48 h showed a 3.5-fold decrease in BrdU foci compared with vehicle control cells. The authors take BrdU foci as a marker of replication fork restart.
  • Niraparib treatment of H2452 cells led to a sevenfold increase in γ-H2Ax foci, a marker of DNA damage
  • In H2452 cells (printed as 'H2542' in the text), 3 μM niraparib for 72 h produced threefold more micronuclei and twofold more nuclear bridging
  • H2452 cells treated with niraparib had a ninefold increase in sister chromatid exchanges compared with the vehicle control group
• The authors' conclusion: The authors concluded that PARP inhibitors such as olaparib and niraparib are promising for treating MPM and that clinical trials in this disease would be warranted. They suggested that all MPM may arise from defects in homologous recombination DNA repair.

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: Pleural Mesothelioma, Unresectable, Chemotherapy, BAP1, Ovarian Cancer.

Related studies

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• PARP1 inhibition affects pleural mesothelioma cell viability and uncouples AKT/mTOR axis via SIRT1 — G. Pinton, A.G. Manente, et al. (2013)
• Functional Genomic Screen in Mesothelioma Reveals that Loss of Function of BRCA1-Associated Protein 1 Induces Chemoresistance to Ribonucleotide Reductase Inhibition — A. Okonska, S. Bühler, et al. (2020)
• The Association of BAP1 Loss-of-Function With the Defect in Homologous Recombination Repair and Sensitivity to PARP-Targeted Therapy — H. Yang, D. Xu, et al. (2020)
• Frequent inactivation of the BAP1 gene in epithelioid-type malignant mesothelioma — Y. Yoshikawa, A. Sato, et al. (2012)
• Functional differences between wild-type and mutant-type BRCA1-associated protein 1 tumor suppressor against malignant mesothelioma cells — S. Hakiri, H. Osada, et al. (2015)

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