Despite its survival benefits, responses to DNA-damaging cisplatin-based chemotherapy are variable in muscle-invasive bladder cancer (MIBC) and predictive biomarkers are sought. A new study using genomic and functional approaches now establishes a role for mutations in the nucleotide excision repair (NER) gene ERCC2 in driving cisplatin sensitivity in MIBC.

Although ERCC2 missense mutations have been associated with improved cisplatin response, Li et al. found that the mutational landscape is broad, identifying 37 ERCC2 mutations at 23 amino acid positions across 3 MIBC cohorts. As the functional influence of individual ERCC2 variants on NER capacity, and therefore cisplatin sensitivity, is unknown, a novel microscopy-based assay was developed to measure the NER capacity of ERCC2 mutations observed across cohorts.

Overall, 23 of 26 clinically observed ERCC2 mutations conferred loss of NER function and increased cisplatin sensitivity, consistent with the role of ERCC2 in repair of cisplatin-induced DNA adducts. Additionally, most ERCC2 mutations were located within or adjacent to helicase domains (which couple ATP hydrolysis with DNA duplex unwinding).

Next, the relationship between ERCC2 functional status, inferred using the NER assay, and clinical outcomes was assessed. ERCC2 mutational frequency was significantly divergent between cisplatin responders and nonresponders (38% versus 6%; P < 0.0001), and each cisplatin-responsive ERCC2-mutant tumour harboured a functionally deleterious helicase domain mutation.

Following the finding that most ERCC2 mutations confer NER deficiency and cisplatin sensitivity, the investigators directly measured the effect of an ERCC2 mutation on cisplatin sensitivity in preclinical models. The CRISPR–Cas9-mediated introduction of an ERCC2 mutation into a high-grade bladder transitional cell carcinoma cell line markedly increased cisplatin sensitivity, which was rescued upon re-expression of wild-type ERCC2. Furthermore, in an orthotopic tumour xenograft model in immunodeficient mice, ERCC2-mutant tumours were markedly more sensitive to cisplatin than ERCC2-wild-type tumours, confirming that ERCC2 loss is sufficient to drive cisplatin sensitivity.

the findings support a role for ERCC2 mutational status as a predictive biomarker

Overall, the findings support a role for ERCC2 mutational status as a predictive biomarker to guide precision oncology in MIBC. Indeed, ongoing trials (NCT03609216, NCT02710734 and NCT03558087) are incorporating DNA damage response gene alterations, including ERCC2 mutational status, as prospective biomarkers.