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

Area of Science:

• Oncology
• Pharmacogenomics
• Cancer Genetics

Background:

• Somatic genetic events offer novel cancer treatment strategies.
• Loss of heterozygosity (LOH) at 8p22 in colorectal cancer (CRC) tumors involving NAT2*6 low activity alleles creates a therapeutic vulnerability.
• Tumors with NAT2 loss are sensitive to the cytotoxic substrate 6-(4-aminophenyl)-N-(3,4,5-trimethoxyphenyl)pyrazin-2-amine (APA).

Purpose of the Study:

• To determine if CRC tumors retaining other NAT2 low activity variants after LOH are also sensitive to APA.
• To estimate the number of CRC patients potentially treatable with APA based on NAT2 LOH.
• To develop a clinical assay for assessing NAT2 locus haplotypes in tumors.

Main Methods:

• Analysis of CRC patient cohorts to identify NAT2 allele heterozygosity and LOH.
• Testing the sensitivity of tumor cells with different NAT2 low activity alleles (NAT2*5, NAT2*14, NAT2*7) to APA.
• Development and validation of a long-read sequencing assay for NAT2 haplotype analysis.

Main Results:

• NAT2*5 and NAT2*14 low activity alleles, unlike NAT2*7, exhibit low metabolism and high sensitivity to APA.
• Approximately 24% of CRC tumors analyzed showed NAT2 allele heterozygosity and LOH.
• Over 79,000 CRC patients annually may meet the genetic criteria for this NAT2 LOH therapy.

Conclusions:

• Loss of NAT2 wild-type alleles through LOH in CRC tumors creates a targetable vulnerability for APA therapy.
• Prevalence of specific NAT2 low activity alleles and LOH suggests a significant patient population could benefit from this approach.
• A novel long-read sequencing assay enables clinical assessment of patient eligibility for NAT2 LOH therapy.