Identifying somatic changes in drug transporters using whole genome and transcriptome sequencing data of advanced tumors

Wesley S. van de Geer; Ron H.J. Mathijssen; Job van Riet; Neeltje Steeghs; Mariette Labots; Carla van Herpen; Lot A. Devriese; Vivianne C.G. Tjan-Heijnen; Emile E. Voest; Stefan Sleijfer; John W.M. Martens; Edwin Cuppen; Harmen J.G. van de Werken; Sander Bins

Biomedicine & Pharmacotherapy (Mar 2023)

Identifying somatic changes in drug transporters using whole genome and transcriptome sequencing data of advanced tumors

Wesley S. van de Geer,
Ron H.J. Mathijssen,
Job van Riet,
Neeltje Steeghs,
Mariette Labots,
Carla van Herpen,
Lot A. Devriese,
Vivianne C.G. Tjan-Heijnen,
Emile E. Voest,
Stefan Sleijfer,
John W.M. Martens,
Edwin Cuppen,
Harmen J.G. van de Werken,
Sander Bins

Affiliations

Wesley S. van de Geer: Dept. of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, the Netherlands; Cancer Computational Biology Center, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, the Netherlands; Dept. of Urology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, the Netherlands
Ron H.J. Mathijssen: Dept. of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, the Netherlands
Job van Riet: Dept. of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, the Netherlands; Cancer Computational Biology Center, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, the Netherlands; Dept. of Urology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, the Netherlands
Neeltje Steeghs: Dept. of Medical Oncology, Netherlands Cancer Institute, Antoni van Leeuwenhoek, Amsterdam, the Netherlands
Mariette Labots: Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Medical Oncology, Amsterdam, the Netherlands
Carla van Herpen: Dept. of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands
Lot A. Devriese: Dept. of Medical Oncology, Cancer Center, University Medical Center Utrecht, Utrecht, the Netherlands
Vivianne C.G. Tjan-Heijnen: Dept. of Medical Oncology, GROW, Maastricht University Medical Center, Maastricht, the Netherlands
Emile E. Voest: Dept. of Medical Oncology, Netherlands Cancer Institute, Antoni van Leeuwenhoek, Amsterdam, the Netherlands; Center for Personalized Cancer Treatment, Rotterdam, the Netherlands; Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, the Netherlands
Stefan Sleijfer: Dept. of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, the Netherlands; Center for Personalized Cancer Treatment, Rotterdam, the Netherlands
John W.M. Martens: Dept. of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, the Netherlands
Edwin Cuppen: Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, the Netherlands; Hartwig Medical Foundation, Amsterdam, the Netherlands
Harmen J.G. van de Werken: Cancer Computational Biology Center, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, the Netherlands; Dept. of Urology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, the Netherlands; Dept. of Immunology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, the Netherlands; Correspondence to: Cancer Computational Biology Center & Department of Urology & Department of Immunology, Erasmus MC Cancer Institute, University Medical Center, PO Box 2040', NA-1218, 3000 CA Rotterdam, the Netherlands.
Sander Bins: Dept. of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, the Netherlands; Correspondence to: Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center, PO Box 2040, Nt-558, 3000 CA Rotterdam, the Netherlands.

Journal volume & issue: Vol. 159
p. 114210

Abstract

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Drug resistance is a perpetual problem in cancer therapy with many underlying mechanisms. Alterations in drug transport over the cancer cell membrane can severely alter intratumoral drug exposure, contributing to resistance. Here, we present the somatic mutational landscape of 48 ATP-binding cassette and 416 solute carrier transporter genes in a cohort (CPCT-02; NCT01855477) of 3290 patients with different types of advanced and metastasized cancer through analysis of whole genome and transcriptome sequencing. In order to identify potential stressor mechanisms, we stratified patients based on previous systemic therapies and subsequently investigated the enrichment of mutations and copy-number alterations of transporter genes. In tumors from patients pretreated with protein kinase inhibitors (PKIs), genes encoding for specific copper (SLC31A1 and SLC31A2, χ2-test adjusted p-values: 6.9e-09 and 2.5e-09) and nucleoside transporters (SLC28A2 and SLC28A3, χ2-test adjusted p-values: 3.5e-06 and 6.8e-07) were deleted significantly more frequently than in patients pretreated with chemotherapy. Moreover, we detected 16 transporters that were differentially expressed at RNA level between these treatment groups. These findings contradict mechanisms of selective pressure, as they would be expected to originate during treatment with chemotherapy rather than with PKIs. Hence, they might constitute primary drug resistance mechanisms and, therefore, warrant further study.

Published in Biomedicine & Pharmacotherapy

ISSN: 0753-3322 (Print); 1950-6007 (Online)
Publisher: Elsevier
Country of publisher: France
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.journals.elsevier.com/biomedicine-and-pharmacotherapy

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