Clin Cancer Res ; 27 7 :04 However, a significant subset of patients is ineligible to receive cisplatin-based therapy due to medical contraindications, and no NER-targeted approaches are available for platinum-ineligible or platinum-refractory ERCC2-mutant cases.
In addition, we used available clinical and sequencing data from multiple urothelial tumor cohorts to develop and validate a composite mutational signature of ERCC2 deficiency and cisplatin sensitivity. Irofulven specifically targets cells with inactivation of the transcription-coupled NER TC-NER pathway and leads to robust responses in vitro and in vivo, including in models with acquired cisplatin resistance, while having minimal effect on cells with intact NER.
We also found that a composite mutational prostate tumour marker of ERCC2 deficiency was strongly prostate tumour marker with cisplatin response in patients and was also associated with prostate tumour marker and irofulven sensitivity in preclinical models.
A composite mutational signature of NER deficiency may be useful in identifying patients likely to respond to NER-targeting agents, including cisplatin and irofulven. See related commentary by Jiang and Greenberg, p.