GSE144761 Targeting Germline and Tumor Associated Nucleotide Excision Repair Defects in Cancer

Contributors : Sabine Topka ; Zoe Steinsnyder ; Vignesh Ravichandran ; Kaitlyn Tkachuk ; Yelena Kemel ; Chaitanya Bandlamudi ; Mogens W Madsen ; Helena Furberg ; Ouathek Ouerfelli ; Charles M Rudin ; Gopakumar Iyer ; Steven M Lipkin ; Semanti Mukherjee ; David B Solit ; Michael F Berger ; Dean F Bajorin ; Jonathan Rosenberg ; Barry S Taylor ; Elisa DeStanchina ; Vijai Joseph ; Kenneth OffitSeries Type : Expression profiling by high throughput sequencingOrganism : Homo sapiensGenetic alterations in members of the nucleotide excision repair (NER) pathway are present in a wide spectrum of cancers, but specific treatment options for this patient population are scarce. Here, we show occurrence of putative damaging germline and somatic alterations in NER genes in up to 10% of patients within certain cancer types across a large set of cancers and explored the potential therapeutic role of irofulven for patients with hypomorphic mutations in nucleotide excision repair genes. Gene-edited isogenic pairs of wildtype and mutant ERCC2 or ERCC3 cell lines were used to assess response to irofulven. Both in vitro and in vivo studies showed significantly enhanced irofulven sensitivity in cells harboring specific clinically observed heterozygous mutations in ERCC2 or ERCC3. Sensitivity of NER mutants to irofulven was greater than to the current standard of care agent cisplatin. Hypomorphic ERCC2/3 mutant cells had an impaired ability to repair irofulven induced DNA damage. Transc...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Homo sapiens Source Type: research