Abstract LB-A07: Targeting nucleotide excision repair defects in cancer

A proportion of cancer patients carry inherited pathogenic variants or somatic alterations in the DNA helicase genes ERCC2 and ERCC3, important components of the nucleotide excision repair (NER) pathway. Cancer risk associated with mutations in nucleotide excision repair is not very well understood and there are no targeted therapies available for patients with NER gene mutations. We have recently shown that functionally significant cancer-associated mutations in ERCC3 exhibit remarkable sensitivity against the fungal sesquiterpene IlludinS. Irofulven, a derivative of IlludinS, has previously been evaluated as an antitumor agent in multiple clinical trials and has shown antitumor activity in a subset of patients. Based on the observation that ERCC3 mutant cell lines are highly sensitive to IlludinS we explored the role of Irofulven as a potential therapeutic agent to treat patients with hypomorphic mutations in nucleotide excision repair genes. We used CRISPR/Cas9 to create isogenic pairs of wildtype and mutant ERCC2 or ERCC3 cell lines and assessed in vitro and in vivo response to Irofulven. In vitro studies showed significantly increased sensitivity of the ERCC3 mutant cells towards Irofulven, when compared to commonly used drugs such as PARP inhibitors or alkylating agents. ERCC2 mutant cells showed elevated in vitro sensitivity to Irofulven even surpassing response to the current standard of care agent Cisplatin. Additionally, in vitro experiments show impaired ability of ERCC2/3 mutant cells to repair Irofulven induced DNA damage. The enhanced Irofulven sensitivity of ERCC3 mutants was replicated in vivo by xenograft experiments. Transcriptome analyses of the tumor tissues gave insights into pathways deregulated in the mutant background and revealed novel biology mediating Irofulven sensitivity suggesting potential for the development of combinatorial therapies. Similar to tumors arising in the background of homologous repair defects, mutations in nucleotide excision repair genes such as ERCC2 and ERCC3 could constitute potential biomarkers of therapeutic response. The present study provides pre-clinical evidence that a subset of tumors with mutations in nucleotide excision repair pathway genes exhibits exceptional sensitivity to Irofulven. Citation Format: Sabine Topka, Zoe Steinsnyder, Kaitlyn Tkachuk, Vignesh Ravichandran, Mogens Winkel Madsen, Helena Furberg-Barnes, Gopakumar Iyer, Elisa De Stanchina, Vijai Joseph, Kenneth Offit. Targeting nucleotide excision repair defects in cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-A07. doi:10.1158/1535-7163.TARG-19-LB-A07