BRCA1/MAD2L1 Deficiency Disrupts the Spindle Assembly Checkpoint to Confer Vinorelbine Resistance in Mesothelioma

Our plain-English summary of BRCA1/MAD2L1 Deficiency Disrupts the Spindle Assembly Checkpoint to Confer Vinorelbine Resistance in Mesothelioma, by S. Busacca, L. O'Regan, A. Singh, et al (Molecular Cancer Therapeutics, 2021).

The study

• Authors: S. Busacca, L. O'Regan, A. Singh, A.J. Sharkey, A.G. Dawson, J. Dzialo, A. Parsons, N. Kumar, L.M. Schunselaar, N. Guppy, A. Nakas, M. Sheaff, A.S. Mansfield, S.M. Janes, P. Baas, A.M. Fry, D.A. Fennell
• Journal: Molecular Cancer Therapeutics
• Published: 2021;20(2):379-388
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Mesothelioma is a universally lethal cancer lacking effective therapy. The spindle poison vinorelbine exhibits clinical activity in the relapsed setting, and in preclinical models requires BRCA1 to initiate apoptosis. However, the mechanisms underlying this regulation and the clinical implications have not been explored. Here, we show that BRCA1 silencing abrogated vinorelbine-induced cell-cycle arrest, recruitment of BUBR1 to kinetochores, and apoptosis. BRCA1 silencing led to codepletion of MAD2L1 at the mRNA and protein levels consistent with its status as a transcriptional target of BRCA1 Silencing of MAD2L1 phenocopied BRCA1 and was sufficient to confer resistance to vinorelbine. This was recapitulated in cell lines selected for resistance to vinorelbine, which acquired loss of both BRCA1 and MAD2L1 expression. Following ex vivo vinorelbine in 20 primary tumor explants, apoptotic response rate was 59% in BRCA1/MAD2L1-positive explants compared with 0% in BRCA1/MAD2L1-negative explants. In 48 patients, BRCA1 and/or MAD2L1 loss of expression was not prognostic; however, in a subset of patients treated with vinorelbine, survival was shorter for patients lacking BRCA1/MAD2L1 expression compared with double-positive patients (5.9 vs. 36.7 months, P = 0.03). Our data implicate BRCA1/MAD2L1 loss as a putative predictive marker of resistance to vinorelbine in mesothelioma and warrant prospective clinical evaluation.

©2020 American Association for Cancer Research.

In plain English

This laboratory study asked why some mesotheliomas may resist vinorelbine, a chemotherapy drug that disrupts cell division. In two mesothelioma cell lines, the authors switched off the BRCA1 gene. The cells then no longer paused in division, and significantly fewer died when given vinorelbine. Switching off BRCA2 did not significantly reduce vinorelbine-induced cell death. Switching off BRCA1 also lowered MAD2L1, a cell-division checkpoint protein, and switching off MAD2L1 alone also protected cells from the drug. Cell lines selected to resist vinorelbine had lower BRCA1 and MAD2L1. In tumour tissue from 20 patients with epithelioid pleural mesothelioma, treated with vinorelbine in the laboratory, 10 of 17 BRCA1-positive samples (59%) showed cell death, versus none of 3 samples negative for BRCA1 or MAD2L1. In 48 archived tumour samples, BRCA1 and MAD2L1 were not linked to survival overall. Among 10 patients given second-line vinorelbine, median survival was 5.9 months for 6 lacking BRCA1 and/or MAD2L1 versus 36.7 months for 4 positive for both (p=0.03). The authors concluded this loss may mark vinorelbine resistance and warrants clinical testing. They noted some analyses were limited by small sample sizes.

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: experiments in mesothelioma cell lines (gene silencing and drug-resistant lines), drug treatment of live tumour tissue samples (explants) from patients, and staining of archived tumour samples compared with patient survival
• Who was studied: Two mesothelioma cell lines (MSTO-211H and REN) and vinorelbine-resistant versions of them (MVR and RVR); live tumour explants from 20 patients with epithelioid malignant pleural mesothelioma having extended pleurectomy and decortication; 48 archived mesothelioma tissue samples from 3 centres (UCL, Mayo Clinic, NKI), 10 of them from patients treated with second-line vinorelbine
• Exposure: The chemotherapy drug vinorelbine (50 nM for REN cells, 100 nM for MSTO-211H cells, 20 nM for imaging and cell-cycle tests, 1 µM for 72 hours in explants), and docetaxel 20 nM; no asbestos exposure was studied
• Main results:
  • In both cell lines, switching off BRCA1 removed the build-up of dividing cells normally caused by vinorelbine
  • Switching off BRCA1, but not BRCA2, significantly reduced (did not eliminate) vinorelbine-induced cell death in the cell lines
  • Switching off MAD2L1 with two different siRNAs had the same effect as switching off BRCA1 and protected the cell lines from vinorelbine-induced cell death
  • The vinorelbine-resistant cell lines (MVR and RVR) had significantly lower BRCA1 protein than the parental lines
  • Switching off BRCA1 also significantly reduced cell death in response to docetaxel in the parental MSTO-211H and REN cells
  • Of the 20 explants, 17 were BRCA1-positive and 3 were BRCA1-negative
  • After vinorelbine, cell death in the explants was seen only in BRCA1-positive samples, in 59% of cases (n=10, out of 17 BRCA1-positive); all 3 samples negative for either BRCA1 or MAD2L1 had a 0% response rate
  • In the 48-patient cohort, BRCA1 was lost in 39.6% (n=19), and 68.4% of those (n=13) also lacked MAD2L1
  • In the 48-patient cohort, BRCA1 and MAD2L1 were not prognostic
  • Among 10 patients treated with second-line vinorelbine, median overall survival was 5.9 months for patients classed as BRCA1/MAD2L1 negative (n=6), described under the heading of loss of BRCA1 or MAD2L1, versus 36.7 months for BRCA1/MAD2L1-positive patients (n=4), p=0.03, hazard ratio 3.737
• The authors' conclusion: The authors concluded that BRCA1/MAD2L1 loss is a putative predictive marker of resistance to vinorelbine in mesothelioma, and that this warrants prospective clinical evaluation, planned in the VIM trial
• Limitations the authors state:
  • In the explants, the ROC curves for BRCA1 and MAD2L1 were not statistically significant (BRCA1 AUC 0.853, p 0.057; MAD2L1 AUC 0.792, p 0.186), which the authors attributed probably to the sample size
  • The effect of MAD2L1 negativity alone (n=3) on survival was not statistically significant (p 0.27), which the authors attributed to the very small sample size
  • For the resistant cell lines, the authors could not tell whether resistance came from expansion of a subgroup of cells or from a drug-induced change

Topics

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

Medical terms in this study, explained in our Lexicon: Vinorelbine, Mesothelioma, Apoptosis.

Related studies

• BRCA1 is an essential mediator of vinorelbine-induced apoptosis in mesothelioma — S. Busacca, M. Sheaff, et al. (2012)
• 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)
• BRCA1-Associated Protein 1 (BAP1) Immunohistochemical Expression as a Diagnostic Tool in Malignant Pleural Mesothelioma Classification: A Large Retrospective Study — L. Righi, E. Duregon, et al. (2016)
• The "Brescia panel" (Claudin-4 and BRCA-associated protein 1) in the differential diagnosis of mesotheliomas with epithelioid features versus metastatic carcinomas — L. Bernardi, T. Bizzarro, et al. (2021)
• Rucaparib in patients with BAP1-deficient or BRCA1-deficient mesothelioma (MiST1): an open-label, single-arm, phase 2a clinical trial — D.A. Fennell, A. King, et al. (2021)
• Immunohistochemical detection of MTAP and BAP1 protein loss for mesothelioma diagnosis: Comparison with 9p21 FISH and BAP1 immunohistochemistry — T. Hida, M. Hamasaki, et al. (2017)

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