C. elegans as a platform to characterize the anti-cancer therapeutic CX-5461

New anti-cancer therapeutics require extensive in vivo characterization to identify endogenous and exogenous factors affecting efficacy, measure toxicity and mutagenicity, and to determine genotypes resulting in therapeutic sensitivity or resistance. Here we present the nematode, Caenorhabditis elegans as a platform with which to characterize the properties of anti-cancer therapeutic agents in vivo. We studied the properties of the new anti-cancer therapeutic CX-5461, which is currently in clinical trials for treatment of BRCA-deficient cancers. We found that CX-5461 is a photosensitizer that generates reactive oxygen species when exposed to UVA radiation. CX-5461 is a mutator, resulting in both large copy number variations and a high frequency of single nucleotide variations. Consistent with these mutation types, we found that homology directed repair and translesion synthesis mutants were sensitive to CX-5461 exposure. Together, the data from C. elegans demonstrates that CX-5461 is a multimodal DNA damaging agent with strong similarity to ellipticines, a class of antineoplastic agents and to anthracycline-based chemotherapeutics.