Characterization of the phototoxicity, chemigenetic profile, and mutational signatures of the chemotherapeutic CX-5461 inCaenorhabditis elegans

Abstract

ABSTRACTNew anti-cancer therapeutics require extensivein vivocharacterization to identify endogenous and exogenous factors affecting efficacy, to measure toxicity and mutagenicity, and to determine genotypes resulting in therapeutic sensitivity or resistance. We usedCaenorhabditis elegansas a platform with which to characterize properties of anti-cancer therapeutic agentsin vivo. We generated a map of chemigenetic interactions between DNA damage response mutants and common DNA damaging agents. We used this map to investigate the properties of the new anti-cancer therapeutic CX-5461. We phenocopied the photoreactivity observed in CX-5461 clinical trials and found that CX-5461 generates reactive oxygen species when exposed to UVA radiation. We demonstrated that CX-5461 is a mutator, resulting in both large copy number variations and a high frequency of single nucleotide variations (SNVs). CX-5461-induced SNVs exhibited a distinct mutational signature. Consistent with the wide range of CX-5461-induced mutation types, we found that multiple repair pathways were needed for CX-5461 tolerance. Together, the data fromC. elegansdemonstrate that CX-5461 is a multimodal DNA damaging agent with strong similarity to ellipticines, a class of antineoplastic agents, and to anthracycline-based chemotherapeutics.