BRCA1/MAD2L1 deficiency disrupts the spindle assembly checkpoint to confer vinorelbine resistance in mesothelioma

Sara Busacca, Laura O’Regan, Anita Singh, Annabel J. Sharkey, Alan G. Dawson, Joanna Dzialo, Aimee Parsons, Neelam Kumar, Laurel M. Schunselaar, Naomi Guppy, Apostolos Nakas, Michael Sheaff, Aaron S. Mansfield, Sam M. Janes, Paul Baas, Andrew M. Fry, Dean A. Fennell

Research output: Contribution to journalArticlepeer-review

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 ¼ 0.03). Our data implicate BRCA1/MAD2L1 loss as a putative predictive marker of resistance to vinorelbine in mesothelioma and warrant prospective clinical evaluation.

Original languageEnglish (US)
Pages (from-to)379-388
Number of pages10
JournalMolecular cancer therapeutics
Volume20
Issue number2
DOIs
StatePublished - Feb 1 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'BRCA1/MAD2L1 deficiency disrupts the spindle assembly checkpoint to confer vinorelbine resistance in mesothelioma'. Together they form a unique fingerprint.

Cite this