Loss of heterozygosity of CYP2D6 enhances the sensitivity of hepatocellular carcinomas to talazoparibResearch in context
Xiaonan Zhang,
Natallia Rameika,
Lei Zhong,
Verónica Rendo,
Margus Veanes,
Snehangshu Kundu,
Sandro Nuciforo,
Jordan Dupuis,
Muhammad Al Azhar,
Ioanna Tsiara,
Pauline Seeburger,
Shahed Al Nassralla,
Viktor Ljungström,
Richard Svensson,
Ivaylo Stoimenov,
Per Artursson,
Markus H. Heim,
Daniel Globisch,
Tobias Sjöblom
Affiliations
Xiaonan Zhang
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, SE-751 85, Uppsala, Sweden
Natallia Rameika
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, SE-751 85, Uppsala, Sweden
Lei Zhong
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, SE-751 85, Uppsala, Sweden
Verónica Rendo
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, SE-751 85, Uppsala, Sweden
Margus Veanes
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, SE-751 85, Uppsala, Sweden
Snehangshu Kundu
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, SE-751 85, Uppsala, Sweden
Sandro Nuciforo
Department of Biomedicine, University Hospital and University of Basel, CH-4031, Basel, Switzerland
Jordan Dupuis
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, SE-751 85, Uppsala, Sweden
Muhammad Al Azhar
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, SE-751 85, Uppsala, Sweden
Ioanna Tsiara
Department of Chemistry-BMC, Science for Life Laboratory, Uppsala University, SE-751 23, Uppsala, Sweden
Pauline Seeburger
Department of Chemistry-BMC, Science for Life Laboratory, Uppsala University, SE-751 23, Uppsala, Sweden
Shahed Al Nassralla
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, SE-751 85, Uppsala, Sweden
Viktor Ljungström
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, SE-751 85, Uppsala, Sweden
Richard Svensson
Uppsala Drug Optimization and Pharmaceutical Profiling Facility (UDOPP), SciLifeLab Chemical Biology Consortium Sweden (CBCS), Department of Pharmacy, Uppsala University, 751 23, Uppsala, Sweden; Department of Pharmacy, Uppsala University, Husargatan 3, 751 23, Uppsala, Sweden
Ivaylo Stoimenov
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, SE-751 85, Uppsala, Sweden
Per Artursson
Department of Pharmacy, Uppsala University, Husargatan 3, 751 23, Uppsala, Sweden
Markus H. Heim
Department of Biomedicine, University Hospital and University of Basel, CH-4031, Basel, Switzerland; Clarunis University Center for Gastrointestinal and Liver Diseases, CH-4002, Basel, Switzerland
Daniel Globisch
Department of Chemistry-BMC, Science for Life Laboratory, Uppsala University, SE-751 23, Uppsala, Sweden
Tobias Sjöblom
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, SE-751 85, Uppsala, Sweden; Corresponding author. Rudbeck Laboratory, Dag Hammarskjölds väg 20, SE-751 85, Uppsala, Sweden.
Summary: Background: Loss of heterozygosity (LOH) diminishes genetic diversity within cancer genomes. A tumour arising in an individual heterozygous for a functional and a loss-of-function (LoF) allele of a gene occasionally retain only the LoF allele. This can result in deficiency of specific protein activities in cancer cells, creating unique differences between tumour cells and normal cells of the individual. Such differences may constitute vulnerabilities that can be exploited through allele-specific therapies. Methods: To discover frequently lost genes with prevalent LoF alleles, we mined the 1000 Genomes dataset for SNVs causing protein truncation through base substitution, indels or splice site disruptions, resulting in 60 LoF variants in 60 genes. From these, the variant rs3892097 in the liver enzyme CYP2D6 was selected because it is located within a genomic region that frequently undergoes LOH in several tumor types including hepatocellular cancers. To evaluate the relationship between CYP2D6 activity and the toxicities of anticancer agents, we screened 525 compounds currently in clinical use or undergoing clinical trials using cell model systems with or without CYP2D6 activity. Findings: We identified 12 compounds, AZD-3463, CYC-116, etoposide, everolimus, GDC-0349, lenvatinib, MK-8776, PHA-680632, talazoparib, tyrphostin 9, VX-702, and WZ-3146, using an engineered HEK293T cell model. Of these, talazoparib and MK-8776 demonstrated consistently heightened cytotoxic effects against cells with compromised CYP2D6 activity in engineered hepatocellular cancer cell models. Moreover, talazoparib displayed CYP2D6 genotype dependent effects on primary hepatocellular carcinoma organoids. Interpretation: Exploiting the loss of drug-metabolizing enzyme gene activity in tumor cells following loss of heterozygosity could present a promising therapeutic strategy for targeted cancer treatment. Funding: This work was funded by Barncancerfonden (T.S, PR2022-0099 and PR2020-0171, X.Z, TJ2021-0111), Cancerfonden (T.S, 211719Pj and D.G, 222449Pj), Vetenskapsrådet (T.S, 2020-02371 and D.G, 2020-04707), and the Erling Persson Foundation (T.S, 2020-0037 and T.S, 2023-0113).
