Exploiting loss of heterozygosity for allele-selective colorectal cancer chemotherapy

Veronica Rendo, Ivaylo Stoimenov, André Mateus, Elin Sjöberg, Richard Svensson, Anna-Lena Gustavsson, Lars Johansson, Adrian Ng, Casey OʼBrien, Marios Giannakis, Per Artursson, Peter Nygren, Ian Cheong and Tobias Sjöblom ()
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Veronica Rendo: Uppsala University
Ivaylo Stoimenov: Uppsala University
André Mateus: Uppsala University
Elin Sjöberg: Uppsala University
Richard Svensson: Uppsala University
Anna-Lena Gustavsson: Karolinska Institute
Lars Johansson: Karolinska Institute
Adrian Ng: Temasek Life Sciences Laboratory, 1 Research Link, NUS
Casey OʼBrien: Dana-Farber Cancer Institute
Marios Giannakis: Dana-Farber Cancer Institute
Per Artursson: Uppsala University
Peter Nygren: Uppsala University
Ian Cheong: Temasek Life Sciences Laboratory, 1 Research Link, NUS
Tobias Sjöblom: Uppsala University

Nature Communications, 2020, vol. 11, issue 1, 1-10

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-15111-4

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