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Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
Published on: September 30, 2016
Exploiting loss of heterozygosity for allele-selective colorectal cancer chemotherapy
Veronica Rendo1,2, Ivaylo Stoimenov1, André Mateus3
1Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, SE-75185, Uppsala, Sweden.
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.
Insights
Targeting cancer chemotherapy by exploiting genetic variations in drug metabolism, like NAT2, offers a new therapeutic strategy. This approach can alter drug efficacy, showing promise for personalized cancer treatment.
Area of Science:
- Oncology
- Pharmacogenomics
- Molecular Biology
Background:
- Cancer cells often exhibit loss of heterozygosity, leading to altered enzyme activity compared to normal cells.
- Identifying genetic variations near enzyme active sites can reveal potential therapeutic targets.
Purpose of the Study:
- To identify non-synonymous small nucleotide variations (nsSNVs) in enzymes frequently lost in cancer.
- To explore the therapeutic potential of targeting enzymes with reduced activity in cancer cells.
Main Methods:
- Mapping genetic polymorphisms to protein structures to identify nsSNVs near catalytic sites.
- Screening small molecules to find inhibitors effective against cells with specific enzyme variants.
- Testing drug sensitivity in patient-derived colorectal cancer (CRC) cells with varying NAT2 activity.
Main Results:
- Identified 45 nsSNVs in 17 enzymes frequently lost in cancer.
- Discovered a kinase inhibitor that impairs growth in cells with slow NAT2 activity.
- Demonstrated that slow NAT2 expression in CRC cells correlates with sensitivity to specific drug treatments.
Conclusions:
- Targeting enzymes with altered activity due to genetic variations is a viable strategy in cancer chemotherapy.
- Bystander mutations in drug metabolic genes can significantly influence the therapeutic index of anti-cancer drugs.
- Personalized approaches considering pharmacogenomic profiles may enhance cancer treatment efficacy.
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