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

Abstract 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...

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Main Authors: Veronica Rendo, Snehangshu Kundu, Natallia Rameika, Viktor Ljungström, Richard Svensson, Kimmo Palin, Lauri Aaltonen, Ivaylo Stoimenov, Tobias Sjöblom
Format: Article
Language:English
Published: Nature Publishing Group 2020-12-01
Series:Scientific Reports
Online Access:https://doi.org/10.1038/s41598-020-80288-z
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spelling doaj-0075eeada5c6431e9aaae378bc12e7b82021-01-03T12:16:31ZengNature Publishing GroupScientific Reports2045-23222020-12-0110111310.1038/s41598-020-80288-zDefining eligible patients for allele-selective chemotherapies targeting NAT2 in colorectal cancerVeronica Rendo0Snehangshu Kundu1Natallia Rameika2Viktor Ljungström3Richard Svensson4Kimmo Palin5Lauri Aaltonen6Ivaylo Stoimenov7Tobias Sjöblom8Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala UniversityScience for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala UniversityScience for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala UniversityScience for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala UniversityUppsala Drug Optimization and Pharmaceutical Profiling Facility (UDOPP), SciLifeLab Chemical Biology Consortium Sweden (CBCS), Department of Pharmacy, Uppsala UniversityApplied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, Biomedicum HelsinkiApplied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, Biomedicum HelsinkiScience for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala UniversityScience for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala UniversityAbstract 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.https://doi.org/10.1038/s41598-020-80288-z
collection DOAJ
language English
format Article
sources DOAJ
author Veronica Rendo
Snehangshu Kundu
Natallia Rameika
Viktor Ljungström
Richard Svensson
Kimmo Palin
Lauri Aaltonen
Ivaylo Stoimenov
Tobias Sjöblom
spellingShingle Veronica Rendo
Snehangshu Kundu
Natallia Rameika
Viktor Ljungström
Richard Svensson
Kimmo Palin
Lauri Aaltonen
Ivaylo Stoimenov
Tobias Sjöblom
Defining eligible patients for allele-selective chemotherapies targeting NAT2 in colorectal cancer
Scientific Reports
author_facet Veronica Rendo
Snehangshu Kundu
Natallia Rameika
Viktor Ljungström
Richard Svensson
Kimmo Palin
Lauri Aaltonen
Ivaylo Stoimenov
Tobias Sjöblom
author_sort Veronica Rendo
title Defining eligible patients for allele-selective chemotherapies targeting NAT2 in colorectal cancer
title_short Defining eligible patients for allele-selective chemotherapies targeting NAT2 in colorectal cancer
title_full Defining eligible patients for allele-selective chemotherapies targeting NAT2 in colorectal cancer
title_fullStr Defining eligible patients for allele-selective chemotherapies targeting NAT2 in colorectal cancer
title_full_unstemmed Defining eligible patients for allele-selective chemotherapies targeting NAT2 in colorectal cancer
title_sort defining eligible patients for allele-selective chemotherapies targeting nat2 in colorectal cancer
publisher Nature Publishing Group
series Scientific Reports
issn 2045-2322
publishDate 2020-12-01
description Abstract 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.
url https://doi.org/10.1038/s41598-020-80288-z
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