Data from Targeting Germline- and Tumor-Associated Nucleotide Excision Repair Defects in Cancer

Abstract

<div>AbstractPurpose:<p>Nucleotide excision repair (NER) gene alterations constitute potential cancer therapeutic targets. We explored the prevalence of NER gene alterations across cancers and putative therapeutic strategies targeting these vulnerabilities.</p>Experimental Design:<p>We interrogated our institutional dataset with mutational data from more than 40,000 patients with cancer to assess the frequency of putative deleterious alterations in four key NER genes. Gene-edited isogenic pairs of wild-type and mutant <i>ERCC2</i> or <i>ERCC3</i> cell lines were created and used to assess response to several candidate drugs.</p>Results:<p>We found that putative damaging germline and somatic alterations in NER genes were present with frequencies up to 10% across multiple cancer types. Both <i>in vitro</i> and <i>in vivo</i> studies showed significantly enhanced sensitivity to the sesquiterpene irofulven in cells harboring specific clinically observed heterozygous mutations in <i>ERCC2</i> or <i>ERCC3</i>. Sensitivity of NER mutants to irofulven was greater than to a current standard-of-care agent, cisplatin. Hypomorphic <i>ERCC2/3</i>-mutant cells had impaired ability to repair irofulven-induced DNA damage. Transcriptomic profiling of tumor tissues suggested codependencies between DNA repair pathways, indicating a potential benefit of combination therapies, which were confirmed by <i>in vitro</i> studies.</p>Conclusions:<p>These findings provide novel insights into a synthetic lethal relationship between clinically observed NER gene deficiencies and sensitivity to irofulven and its potential synergistic combination with other drugs.</p><p><i>See related commentary by Jiang and Greenberg, p. 1833</i></p></div>