TY  - JOUR
A1  - Dietrich, Sascha
A1  - Oleś, Małgorzata
A1  - Lu, Junyan
A1  - Sellner, Leopold
A1  - Anders, Simon
A1  - Velten, Britta
A1  - Wu, Bian
A1  - Hüllein, Jennifer
A1  - Silva Liberio, Michelle da
A1  - Walther, Tatjana
A1  - Wagner, Lena
A1  - Rabe, Sophie
A1  - Ghidelli-Disse, Sonja
A1  - Bantscheff, Marcus
A1  - Oleś, Andrzej K.
A1  - Słabicki, Mikołaj
A1  - Mock, Andreas
A1  - Oakes, Christopher C.
A1  - Wang, Shihui
A1  - Oppermann, Sina
A1  - Lukas, Marina
A1  - Kim, Vladislav
A1  - Sill, Martin
A1  - Benner, Axel
A1  - Jauch, Anna
A1  - Sutton, Lesley-Ann
A1  - Young, Emma
A1  - Rosenquist, Richard
A1  - Liu, Xiyang
A1  - Jethwa, Alexander
A1  - Lee, Kwang Seok
A1  - Lewis, Joe
A1  - Putzker, Kerstin
A1  - Lutz, Christoph
A1  - Rossi, Davide
A1  - Mokhir, Andriy
A1  - Oellerich, Thomas
A1  - Zirlik, Katja
A1  - Herling, Marco
A1  - Nguyen-Khac, Florence
A1  - Plass, Christoph
A1  - Andersson, Emma
A1  - Mustjoki, Satu
A1  - Kalle, Christof von
A1  - Ho, Anthony Dick
A1  - Hensel, Manfred
A1  - Dürig, Jan
A1  - Ringshausen, Ingo
A1  - Zapatka, Marc
A1  - Huber, Wolfgang
A1  - Zenz, Thorsten
T1  - Drug-perturbation-based stratification of blood cancer
T2  - The journal of clinical investigation
N2  - 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.
KW  - B cell receptor
KW  - Drug screens
KW  - Hematology
KW  - Leukemias
KW  - Oncology
Y1  - 2017
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/50259
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-502597
SN  - 1558-8238
SN  - 0021-9738
N1  - License: This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
VL  - 128
IS  - 1
SP  - 427
EP  - 445
PB  - ASCJ
CY  - Ann Arbor, Mich.
ER  -