Journal Article

Exploiting loss of heterozygosity for allele-selective colorectal cancer chemotherapy

Artursson, Per, Mateus, André, Cheong, Ian, OʼBrien, Casey, Gustavsson, Anna-Lena, Giannakis, Marios, Ng, Adrian, Johansson, Lars, Stoimenov, Ivaylo, Nygren, Peter, Sjöblom, Tobias, Rendo, Veronica, Sjöberg, Elin, Svensson, Richard

2020

Overview

Cancer chemotherapy targeting frequent loss of heterozygosity events is an attractive concept, since tumor cells may lack enzymatic activities present in normal constitutional cells. To find exploitable targets, we map prevalent genetic polymorphisms to protein structures and identify 45 nsSNVs (non-synonymous small nucleotide variations) near the catalytic sites of 17 enzymes frequently lost in cancer. For proof of concept, we select the gastrointestinal drug metabolic enzyme NAT2 at 8p22, which is frequently lost in colorectal cancers and has a common variant with 10-fold reduced activity. Small molecule screening results in a cytotoxic kinase inhibitor that impairs growth of cells with slow NAT2 and decreases the growth of tumors with slow NAT2 by half as compared to those with wild-type NAT2. Most of the patient-derived CRC cells expressing slow NAT2 also show sensitivity to 6-(4-aminophenyl)-N-(3,4,5-trimethoxyphenyl)pyrazin-2-amine (APA) treatment. These findings indicate that the therapeutic index of anti-cancer drugs can be altered by bystander mutations affecting drug metabolic genes. Allelic losses occurring in cancer cells have been suggested as potential targets for therapy. Here, the authors show how recurring loss of heterozygosity of a drug metabolic gene in colorectal cancers can be exploited using a low molecular weight compound.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/58 / 13/106 / 13/109 / 14/1 / 14/19 / 38/77 / 38/88 / 38/89 / 45/23 / 49/98 / 631/154/1435/2417 / 631/67/1059/602 / 631/67/1504/1885/1393 / 64/60 / Active sites / Alleles / Animals / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Arylamine N-Acetyltransferase - genetics / Arylamine N-Acetyltransferase - metabolism / Bystander Effect - genetics / Cancer / Cancer therapies / Case-Control Studies / Chemotherapy / Colorectal cancer / Colorectal carcinoma / Colorectal Neoplasms - drug therapy / Colorectal Neoplasms - genetics / Colorectal Neoplasms - pathology / Cytotoxicity / Dose-Response Relationship, Drug / Enzymatic activity / Enzyme inhibitors / Female / HCT116 Cells / Heterozygosity / Humanities and Social Sciences / Humans / Isoenzymes - metabolism / Kinases / Loss of Heterozygosity / Low molecular weights / Metabolism / Mice / Mice, Nude / Molecular weight / multidisciplinary / Mutation / Nucleotides / Polymorphism, Genetic / Protein Kinase Inhibitors - pharmacology / Protein Kinase Inhibitors - therapeutic use / Science / Science (multidisciplinary) / Small Molecule Libraries / Tumor cells / Tumors / Xenograft Model Antitumor Assays