Defining eligible patients for allele-selective chemotherapies targeting NAT2 in colorectal cancer

Sci Rep. 2020 Dec 31;10(1):22436. doi: 10.1038/s41598-020-80288-z.


Therapies targeting somatic bystander genetic events represent a new avenue for cancer treatment. We recently identified a subset of colorectal cancer (CRC) patients who are heterozygous for a wild-type and a low activity allele (NAT2*6) but lack the wild-type allele in their tumors due to loss of heterozygosity (LOH) at 8p22. These tumors were sensitive to treatment with a cytotoxic substrate of NAT2 (6-(4-aminophenyl)-N-(3,4,5-trimethoxyphenyl)pyrazin-2-amine, APA), and pointed to NAT2 loss being a therapeutically exploitable vulnerability of CRC tumors. To better estimate the total number of treatable CRC patients, we here determined whether tumor cells retaining also other NAT2 low activity variants after LOH respond to APA treatment. The prevalent low activity alleles NAT2*5 and NAT2*14, but not NAT2*7, were found to be low metabolizers with high sensitivity to APA. By analysis of two different CRC patient cohorts, we detected heterozygosity for NAT2 alleles targetable by APA, along with allelic imbalances pointing to LOH, in ~ 24% of tumors. Finally, to haplotype the NAT2 locus in tumor and patient-matched normal samples in a clinical setting, we develop and demonstrate a long-read sequencing based assay. In total, > 79.000 CRC patients per year fulfil genetic criteria for high sensitivity to a NAT2 LOH therapy and their eligibility can be assessed by clinical sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles*
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Arylamine N-Acetyltransferase / antagonists & inhibitors*
  • Arylamine N-Acetyltransferase / genetics*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics*
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use*
  • Gene Frequency
  • Haplotypes
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Molecular Targeted Therapy*
  • Phenotype
  • Single Molecule Imaging


  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Arylamine N-Acetyltransferase
  • NAT2 protein, human