reports demonstrating that BRCA1 expression is required for response to anti microtubule agents including vinorelbine. We report that loss of BRCA1 can be acquired during selection for vinorelbine resistance. Chemoresistance associated loss of BRCA1 has been previously reported in a study in which gene expression analysis demonstrated BRCA1 downregulationin cells selected Nepafenac for resistance to the microtubule stabilizing agent discodermolide. In addition, we demonstrate that re expression of BRCA1 in vinorelbine resistant cells is sufficient to restore sensitivity. This is consistent with previously reported data demonstrating that reconstitution of wild type BRCA1 expression in BRCA1 mutated breast cancer cell lines results in an increase in response to both paclitaxel and vinorelbine.
Other factors are likely to play a role in mediating resistance to vinorelbine. Overexpression of the drug efflux transporters of the ATP binding cassette family, ABCB1/MDR1 and ABCC10/MRP7, in NSCLC has been implicated in resistance. The non ATP binding parthenolide (-)-Parthenolide cassette transport protein RLIP76 has also been reported to lead to resistance to vinorelbine due to reduced drug accumulation, as evidenced in NSCLC. Finally, high levels of expression of class III tubulin in tumour cells have been associated with mechanisms of resistance to tubulin binding agents including vinorelbine. These potential multifactorial mechanisms of vinorelbine resistance may perhaps explain our inability to fully restore sensitivity, with the BRCA1 plasmid, to the levels observed in REN and MSTO 211H parental cells.
Nonetheless, our data demonstrating the significant reduction of BRCA1 expression consequent to the induction of resistance to vinorelbine strongly support the role of BRCA1 expression as an c-Met Signaling Pathway essential mediator of response to vinorelbine treatment in malignant mesothelioma. Personalizing treatment with vinorelbine based on predictive biomarkers of efficacy could facilitate the approval of vinorelbine in a randomized clinical study. We therefore proceeded with a retrospective analysis in order to identify whether a subset of primary MPM tumours exhibited loss of BRCA1 expression as a basis for considering BRCA1 as a potentially useful biomarker. Our findings confirm that a significant proportion of MPM, approximately one third, are BRCA1 immunonegative.
This fgfr proportion is clinically significant and could potentially influence the outcome of therapy in an unselected population. However, evidence institutionalized of a clear correlation between BRCA1 expression and response to vinorelbine was not possible due to limited access to sufficient numbers of samples, inherent limitations related to statistical power and therefore interpretation, and reliable retrospective clinical data associated ideally with a durable radiological response reported in a clinical trial of vinorelbine monotherapy. The assessment of a correlation between vinorelbine sensitivity and BRCA1 expression is being addressed in a national UK clinical trial which is currently under development. This trial will aim to provide the clinical proof of concept that BRCA1 deficiency is associated with a lack of clinical efficacy. The use of an immunohistochemical assay to assess expression provides a versatile method for the screening.