The chemotherapeutic CX-5461 is extremely mutagenic and may increase cancer risk
The chemotherapeutic agent CX-5461 or pidnarulex has been fast-tracked by the US FDA for treatment of BRCA1-, BRCA2-, and PALB2-mutated cancers. It is under investigation in Phase I/II clinical trials. Here we find that although CX-5461 exhibits synthetic lethality in BRCA1-/BRCA2-deficient cells, it also causes extensive, non-selective, collateral mutagenesis in all cells, to magnitudes that exceed known environmental carcinogens, raising public health concerns regarding its potential for promoting secondary cancers. Deposited here are the de novo mutation lists from the experimental samples included in the study. Whole-genome sequencing short reads were aligned to GRCh38/hg38 using BWA-MEM. Post-processing filters were applied to improve the specificity of mutation-calling. Specifically, for single nucleotide variant calls by CaVEMan, we used CLPM == 0 and ASMD >= 140. To reduce false positive calls by Pindel, we used QUAL >= 250 and REP < 10. Rearrangements were not assessed as they were too few to be informative. A filter for variant allele frequency (> 0.2) was applied to substitutions and indels. De novo substitutions and indels in subclones were obtained by subtracting from respective parental clone whenever available, or by removing mutations shared among subclones. TwinStrand duplex sequencing data were analysed with the TwinStrand DuplexSeq Mutagenesis App, hosted on DNAnexus. The Mutagenesis App performed error-correction and generated Duplex Consensus alignment and variant calls for both germline and ultra-rare somatic variants. Only variants with variant allele frequency < 0.01 were considered to be the result of mutagenesis (i.e., mutation), and included for subsequent mutation burden and signature analysis. Provided here are the mutation calls from both iPS and HAP1 cells.