TY - JOUR
T1 - Identifying somatic changes in drug transporters using whole genome and transcriptome sequencing data of advanced tumors
AU - van de Geer, Wesley S.
AU - Mathijssen, Ron H. J.
AU - van Riet, Job
AU - Steeghs, Neeltje
AU - Labots, Mariette
AU - van Herpen, Carla
AU - Devriese, Lot A.
AU - Tjan-Heijnen, Vivianne C. G.
AU - Voest, Emile E.
AU - Sleijfer, Stefan
AU - Martens, John W. M.
AU - Cuppen, Edwin
AU - van de Werken, Harmen J. G.
AU - Bins, Sander
N1 - Funding Information: This publication and the underlying study have been made possible partly on the basis of the data that Hartwig Medical Foundation and the Center of Personalized Cancer Treatment (CPCT) have made available to the study. We would like to thank J. Alberto Nakauma-Gonzalez for providing assistance with statistical testing with Poisson distributions. Publisher Copyright: © 2023 The Authors
PY - 2023/3/1
Y1 - 2023/3/1
N2 - 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.
AB - 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.
KW - Drug transporters
KW - Metastatic cancer
KW - Pharmacogenetics
KW - Pharmacogenomics
KW - Precision medicine
KW - RNA sequencing
KW - Whole-genome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85146013143&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.biopha.2022.114210
DO - https://doi.org/10.1016/j.biopha.2022.114210
M3 - Article
C2 - 36621142
SN - 0753-3322
VL - 159
JO - Biomedicine and Pharmacotherapy
JF - Biomedicine and Pharmacotherapy
M1 - 114210
ER -