Drug-perturbation-based stratification of blood cancer

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Dietrich , S , Oles , M , Lu , J , Sellner , L , Anders , S , Velten , B , Wu , B , Huellein , J , Liberio , M D S , Walther , T , Wagner , L , Rabe , S , Ghidelli-Disse , S , Bantscheff , M , Oles , A K , Slabicki , M , Mock , A , Oakes , C C , Wang , S , Oppermann , S , Lukas , M , Kim , V , Sill , M , Benner , A , Jauch , A , Sutton , L A , Young , E , Rosenquist , R , Liu , X , Jethwa , A , Lee , K S , Lewis , J , Putzker , K , Lutz , C , Rossi , D , Mokhir , A , Oellerich , T , Zirlik , K , Herling , M , Nguyen-Khac , F , Plass , C , Andersson , E , Mustjoki , S , von Kalle , C , Ho , A D , Hensel , M , Duerig , J , Ringshausen , I , Zapatka , M , Huber , W & Zenz , T 2018 , ' Drug-perturbation-based stratification of blood cancer ' , Journal of Clinical Investigation , vol. 128 , no. 1 , pp. 427-445 . https://doi.org/10.1172/JCI93801

Title: Drug-perturbation-based stratification of blood cancer
Author: Dietrich, Sascha; Oles, Malgorzata; Lu, Junyan; Sellner, Leopold; Anders, Simon; Velten, Britta; Wu, Bian; Huellein, Jennifer; Liberio, Michelle da Silva; Walther, Tatjana; Wagner, Lena; Rabe, Sophie; Ghidelli-Disse, Sonja; Bantscheff, Marcus; Oles, Andrzej K.; Slabicki, Mikolaj; Mock, Andreas; Oakes, Christopher C.; Wang, Shihui; Oppermann, Sina; Lukas, Marina; Kim, Vladislav; Sill, Martin; Benner, Axel; Jauch, Anna; Sutton, Lesley Ann; Young, Emma; Rosenquist, Richard; Liu, Xiyang; Jethwa, Alexander; Lee, Kwang Seok; Lewis, Joe; Putzker, Kerstin; Lutz, Christoph; Rossi, Davide; Mokhir, Andriy; Oellerich, Thomas; Zirlik, Katja; Herling, Marco; Nguyen-Khac, Florence; Plass, Christoph; Andersson, Emma; Mustjoki, Satu; von Kalle, Christof; Ho, Anthony D.; Hensel, Manfred; Duerig, Jan; Ringshausen, Ingo; Zapatka, Marc; Huber, Wolfgang; Zenz, Thorsten
Contributor organization: Clinicum
Department of Oncology
Hematologian yksikkö
Department of Clinical Chemistry and Hematology
University of Helsinki
HUS Comprehensive Cancer Center
Date: 2018-01-02
Language: eng
Number of pages: 19
Belongs to series: Journal of Clinical Investigation
ISSN: 0021-9738
DOI: https://doi.org/10.1172/JCI93801
URI: http://hdl.handle.net/10138/231773
Abstract: As new generations of targeted therapies emerge and tumor genome sequencing discovers increasingly comprehensive mutation repertoires, the functional relationships of mutations to tumor phenotypes remain largely unknown. Here, we measured ex vivo sensitivity of 246 blood cancers to 63 drugs alongside genome, transcriptome, and DNA methylome analysis to understand determinants of drug response. We assembled a primary blood cancer cell encyclopedia data set that revealed disease-specific sensitivities for each cancer. Within chronic lymphocytic leukemia (CLL), responses to 62% of drugs were associated with 2 or more mutations, and linked the B cell receptor (BCR) pathway to trisomy 12, an important driver of CLL. Based on drug responses, the disease could be organized into phenotypic subgroups characterized by exploitable dependencies on BCR, mTOR, or MEK signaling and associated with mutations, gene expression, and DNA methylation. Fourteen percent of CLLs were driven by mTOR signaling in a non-BCR-dependent manner. Multivariate modeling revealed immunoglobulin heavy chain variable gene (IGHV) mutation status and trisomy 12 as the most important modulators of response to kinase inhibitors in CLL. Ex vivo drug responses were associated with outcome. This study overcomes the perception that most mutations do not influence drug response of cancer, and points to an updated approach to understanding tumor biology, with implications for biomarker discovery and cancer care.
3122 Cancers
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion

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