Clonal heterogeneity influences drug responsiveness in renal cancer assessed by ex vivo drug testing of multiple patient‐derived cancer cells

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Sammanfattning

Renal cell cancer (RCC) has become a prototype example of the extensive intratumor heterogeneity and clonal evolution of human cancers. However, there is little direct evidence on how the genetic heterogeneity impacts on drug response profiles of the cancer cells. Our goal was to determine how genomic clonal evolution impacts drug responses. Finding from our study could help to define the challenge that clonal evolution poses on cancer therapy. We established multiple patient-derived cells (PDCs) from different tumor regions of four RCC patients, verified their clonal relationship to each other and to the uncultured tumor tissue by genome sequencing. Furthermore, comprehensive drug-sensitivity testing with 460 oncological drugs was performed on all PDC clones. The PDCs retained many cancer-specific copy number alterations and mutations in driver genes such as VHL, PBRM1, PIK3C2A, KMD5C and TSC2 genes. The drug testing highlighted vulnerability in the PDCs toward approved RCC drugs, such as the mTOR-inhibitor temsirolimus, but also novel sensitivities were uncovered. The individual PDC clones from different tumor regions in a patient showed distinct drug-response profiles, suggesting that genomic heterogeneity contributes to the variability in drug responses. Studies of multiple PDCs from a patient with cancer are informative for elucidating cancer heterogeneity and for the determination on how the genomic evolution is manifested in cancer drug responsiveness. This approach could facilitate tailoring of drugs and drug combinations to individual patients.

Originalspråkengelska
TidskriftInternational Journal of Cancer
Volym144
Utgåva6
Sidor (från-till)1356-1366
Antal sidor11
ISSN0020-7136
DOI
StatusPublicerad - 15 mar 2019
MoE-publikationstypA1 Tidskriftsartikel-refererad

Vetenskapsgrenar

  • 3122 Cancersjukdomar

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@article{240b284783a042ee88ef190d417c26eb,
title = "Clonal heterogeneity influences drug responsiveness in renal cancer assessed by ex vivo drug testing of multiple patient‐derived cancer cells",
abstract = "Renal cell cancer (RCC) has become a prototype example of the extensive intratumor heterogeneity and clonal evolution of human cancers. However, there is little direct evidence on how the genetic heterogeneity impacts on drug response profiles of the cancer cells. Our goal was to determine how genomic clonal evolution impacts drug responses. Finding from our study could help to define the challenge that clonal evolution poses on cancer therapy. We established multiple patient-derived cells (PDCs) from different tumor regions of four RCC patients, verified their clonal relationship to each other and to the uncultured tumor tissue by genome sequencing. Furthermore, comprehensive drug-sensitivity testing with 460 oncological drugs was performed on all PDC clones. The PDCs retained many cancer-specific copy number alterations and mutations in driver genes such as VHL, PBRM1, PIK3C2A, KMD5C and TSC2 genes. The drug testing highlighted vulnerability in the PDCs toward approved RCC drugs, such as the mTOR-inhibitor temsirolimus, but also novel sensitivities were uncovered. The individual PDC clones from different tumor regions in a patient showed distinct drug-response profiles, suggesting that genomic heterogeneity contributes to the variability in drug responses. Studies of multiple PDCs from a patient with cancer are informative for elucidating cancer heterogeneity and for the determination on how the genomic evolution is manifested in cancer drug responsiveness. This approach could facilitate tailoring of drugs and drug combinations to individual patients.",
keywords = "renal carcinoma, patient-derived cells, drug sensitivity testing, intratumor heterogeneity, subclones, precision medicine, TUMOR-SUPPRESSOR PROTEIN, CARCINOMA, INHIBITOR, CULTURES, EVOLUTION, STRATEGY, MODELS, 3122 Cancers",
author = "Khalid Saeed and Poojitha Ojamies and Teijo Pellinen and Samuli Eldfors and Riku Turkki and Johan Lundin and Petrus J{\"a}rvinen and Harry Nis{\'e}n and Kimmo Taari and {af H{\"a}llstr{\"o}m}, {Taija Maria} and Antti Rannikko and Tuomas Mirtti and Olli-Pekka Kallioniemi and P{\"a}ivi {\"O}stling",
year = "2019",
month = "3",
day = "15",
doi = "10.1002/ijc.31815",
language = "English",
volume = "144",
pages = "1356--1366",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley",
number = "6",

}

TY - JOUR

T1 - Clonal heterogeneity influences drug responsiveness in renal cancer assessed by ex vivo drug testing of multiple patient‐derived cancer cells

AU - Saeed, Khalid

AU - Ojamies, Poojitha

AU - Pellinen, Teijo

AU - Eldfors, Samuli

AU - Turkki, Riku

AU - Lundin, Johan

AU - Järvinen, Petrus

AU - Nisén, Harry

AU - Taari, Kimmo

AU - af Hällström, Taija Maria

AU - Rannikko, Antti

AU - Mirtti, Tuomas

AU - Kallioniemi, Olli-Pekka

AU - Östling, Päivi

PY - 2019/3/15

Y1 - 2019/3/15

N2 - Renal cell cancer (RCC) has become a prototype example of the extensive intratumor heterogeneity and clonal evolution of human cancers. However, there is little direct evidence on how the genetic heterogeneity impacts on drug response profiles of the cancer cells. Our goal was to determine how genomic clonal evolution impacts drug responses. Finding from our study could help to define the challenge that clonal evolution poses on cancer therapy. We established multiple patient-derived cells (PDCs) from different tumor regions of four RCC patients, verified their clonal relationship to each other and to the uncultured tumor tissue by genome sequencing. Furthermore, comprehensive drug-sensitivity testing with 460 oncological drugs was performed on all PDC clones. The PDCs retained many cancer-specific copy number alterations and mutations in driver genes such as VHL, PBRM1, PIK3C2A, KMD5C and TSC2 genes. The drug testing highlighted vulnerability in the PDCs toward approved RCC drugs, such as the mTOR-inhibitor temsirolimus, but also novel sensitivities were uncovered. The individual PDC clones from different tumor regions in a patient showed distinct drug-response profiles, suggesting that genomic heterogeneity contributes to the variability in drug responses. Studies of multiple PDCs from a patient with cancer are informative for elucidating cancer heterogeneity and for the determination on how the genomic evolution is manifested in cancer drug responsiveness. This approach could facilitate tailoring of drugs and drug combinations to individual patients.

AB - Renal cell cancer (RCC) has become a prototype example of the extensive intratumor heterogeneity and clonal evolution of human cancers. However, there is little direct evidence on how the genetic heterogeneity impacts on drug response profiles of the cancer cells. Our goal was to determine how genomic clonal evolution impacts drug responses. Finding from our study could help to define the challenge that clonal evolution poses on cancer therapy. We established multiple patient-derived cells (PDCs) from different tumor regions of four RCC patients, verified their clonal relationship to each other and to the uncultured tumor tissue by genome sequencing. Furthermore, comprehensive drug-sensitivity testing with 460 oncological drugs was performed on all PDC clones. The PDCs retained many cancer-specific copy number alterations and mutations in driver genes such as VHL, PBRM1, PIK3C2A, KMD5C and TSC2 genes. The drug testing highlighted vulnerability in the PDCs toward approved RCC drugs, such as the mTOR-inhibitor temsirolimus, but also novel sensitivities were uncovered. The individual PDC clones from different tumor regions in a patient showed distinct drug-response profiles, suggesting that genomic heterogeneity contributes to the variability in drug responses. Studies of multiple PDCs from a patient with cancer are informative for elucidating cancer heterogeneity and for the determination on how the genomic evolution is manifested in cancer drug responsiveness. This approach could facilitate tailoring of drugs and drug combinations to individual patients.

KW - renal carcinoma

KW - patient-derived cells

KW - drug sensitivity testing

KW - intratumor heterogeneity

KW - subclones

KW - precision medicine

KW - TUMOR-SUPPRESSOR PROTEIN

KW - CARCINOMA

KW - INHIBITOR

KW - CULTURES

KW - EVOLUTION

KW - STRATEGY

KW - MODELS

KW - 3122 Cancers

U2 - 10.1002/ijc.31815

DO - 10.1002/ijc.31815

M3 - Article

VL - 144

SP - 1356

EP - 1366

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 6

ER -