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

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Saeed , K , Ojamies , P , Pellinen , T , Eldfors , S , Turkki , R , Lundin , J , Järvinen , P , Nisén , H , Taari , K , af Hällström , T M , Rannikko , A , Mirtti , T , Kallioniemi , O-P & Östling , P 2019 , ' Clonal heterogeneity influences drug responsiveness in renal cancer assessed by ex vivo drug testing of multiple patient‐derived cancer cells ' , International Journal of Cancer , vol. 144 , no. 6 , pp. 1356-1366 . https://doi.org/10.1002/ijc.31815

Title: Clonal heterogeneity influences drug responsiveness in renal cancer assessed by ex vivo drug testing of multiple patient‐derived cancer cells
Author: Saeed, Khalid; Ojamies, Poojitha; Pellinen, Teijo; Eldfors, Samuli; Turkki, Riku; Lundin, Johan; Järvinen, Petrus; Nisén, Harry; Taari, Kimmo; af Hällström, Taija Maria; Rannikko, Antti; Mirtti, Tuomas; Kallioniemi, Olli-Pekka; Östling, Päivi
Contributor organization: Institute for Molecular Medicine Finland
University of Helsinki
Johan Edvard Lundin / Principal Investigator
Urologian yksikkö
Department of Surgery
Clinicum
Doctoral Programme in Integrative Life Science
Olli-Pekka Kallioniemi / Principal Investigator
HUS Abdominal Center
Precision Systems Medicine
Date: 2019-03-15
Language: eng
Number of pages: 11
Belongs to series: International Journal of Cancer
ISSN: 0020-7136
DOI: https://doi.org/10.1002/ijc.31815
URI: http://hdl.handle.net/10138/304837
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.
Subject: renal carcinoma
patient-derived cells
drug sensitivity testing
intratumor heterogeneity
subclones
precision medicine
TUMOR-SUPPRESSOR PROTEIN
CARCINOMA
INHIBITOR
CULTURES
EVOLUTION
STRATEGY
MODELS
3122 Cancers
Peer reviewed: Yes
Rights: unspecified
Usage restriction: openAccess
Self-archived version: acceptedVersion


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