IBCN 2020: Improving Methods to Detect and Target Nucleotide Excision Repair Deficiency In Bladder Cancer

(UroToday.com) While cisplatin-based chemotherapy is a first-line treatment for muscle-invasive and metastatic bladder cancer, only a subset of patients responds to therapy. Nearly 15% of urothelial tumors have a somatic missense mutation in ERCC2, a nucleotide excision repair (NER) gene that confers increased sensitivity to cisplatin. However, a significant percentage of patients are ineligible for cisplatin-based therapy due to medical contraindications, and no NER-targeted approaches are available for platinum-ineligible or platinum-refractory ERCC2 mutant cases.

Dr. Mouw presented data from his group that used CRISPR gene-editing technology to create novel NER-deficient/proficient cell pairs and test the impact of NER loss on cellular DNA repair properties and therapeutic sensitivities. They identified a novel synthetic lethal relationship between NER-deficient tumors and sensitivity to irofulven, an abandoned anti-cancer agent previously shown to have only modest activity in Phase I/II trials in biomarker-unselected populations. Irofulven targets cells with inactivation of the transcription-coupled NER pathway and leads to robust responses in vitro and in vivo, including in models with acquired cisplatin resistance (Figure), while having minimal effect on cells with intact NER.

Figure: Irofulven maintains activity in a cisplatin-resistant model.

The authors also developed and validated a composite mutational signature of NER deficiency in bladder cancer that is strongly associated with cisplatin response in bladder cancer including tumors that lack ERCC2 mutation, and is also associated with cisplatin and irofulven sensitivity in preclinical models. This may therefore serve as an additional tool to identify patients likely to respond to NER-targeting agents including cisplatin and irofulven.

Presented by: Kent W Mouw, MD, PhD, Dana-Farber Cancer Institute, Boston, MA, USA.

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