Abstract PR01: A functional variomic chemi-genetic screen in C. elegans identifies new synthetic lethal interactions with PARP inhibition that are conserved from worm to human

Poly ADP-ribose polymerase (PARP) inhibitors are anti-cancer therapeutics that are synthetic lethal (SL) with mutations affecting the homologous recombination genes BRCA1 or BRCA2. Previous work from our lab found that cohesin mutations, which are common in a range of tumour types, also confer sensitivity to PARP inhibition. We want to extend the SL profile of PARP inhibitors to identify the full spectrum of genetic variants that result in sensitivity to PARP inhibitors alone or in combination with DNA damaging agents.To this end, we are using the model organism Caenorhabditis elegans to screen for new SL interactions with PARP inhibitors. C. elegans provides an excellent in vivo system with which to investigate SL interactions with cancer-associated mutations, as many of the pathways and genes implicated in cancer are conserved between humans and C. elegans. In many ways, C. elegans is an animal model that combines the technical advantages of a single celled organism, such as yeast, with increased developmental complexity and a gene complement more akin to humans.We have developed a high throughput in vivo variomics approach using the C. elegans Million Mutation Project strain collection to screen 2,000 mutagenized and sequenced strains containing >800,000 homozygous genetic variations. To date we have found 16 strains that were sensitive to the PARP inhibitor olaparib. Frequency analysis of the variants in the sensitive strains identified multiple mutations affecting mus...
Source: Molecular Cancer Therapeutics - Category: Cancer & Oncology Authors: Tags: Model Organisms to Identify Synthetic Lethal Interactions: Oral Presentations - Proffered Abstracts Source Type: research