Dietrich, Sascha, Oles, Malgorzata, Lu, Junyan ORCID: 0000-0002-9211-0746, Sellner, Leopold ORCID: 0000-0002-7893-401X, Anders, Simon ORCID: 0000-0003-4868-1805, 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 ORCID: 0000-0001-7616-7665, Benner, Axel, Jauch, Anna, Sutton, Lesley Ann, Young, Emma, Rosenquist, Richard, Liu, Xiyang, Jethwa, Alexander ORCID: 0000-0003-3869-8662, Lee, Kwang Seok, Lewis, Joe, Putzker, Kerstin, Lutz, Christoph, Rossi, Davide, Mokhir, Andriy, Oellerich, Thomas, Zirlik, Katja, Herling, Marco, Nguyen-Khac, Florence ORCID: 0000-0003-3107-6668, Plass, Christoph, Andersson, Emma, Mustjoki, Satu ORCID: 0000-0002-0816-8241, von Kalle, Christof, Ho, Anthony D. ORCID: 0000-0002-1656-0833, Hensel, Manfred, Duerig, Jan, Ringshausen, Ingo ORCID: 0000-0002-7247-311X, Zapatka, Marc ORCID: 0000-0001-8287-5967, Huber, Wolfgang ORCID: 0000-0002-0474-2218 and Zenz, Thorsten (2018). Drug-perturbation-based stratification of blood cancer. J. Clin. Invest., 128 (1). S. 427 - 446. ANN ARBOR: AMER SOC CLINICAL INVESTIGATION INC. ISSN 1558-8238

Full text not available from this repository.

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Dietrich, SaschaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oles, MalgorzataUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lu, JunyanUNSPECIFIEDorcid.org/0000-0002-9211-0746UNSPECIFIED
Sellner, LeopoldUNSPECIFIEDorcid.org/0000-0002-7893-401XUNSPECIFIED
Anders, SimonUNSPECIFIEDorcid.org/0000-0003-4868-1805UNSPECIFIED
Velten, BrittaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wu, BianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huellein, JenniferUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liberio, Michelle da SilvaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Walther, TatjanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wagner, LenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rabe, SophieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ghidelli-Disse, SonjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bantscheff, MarcusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oles, Andrzej K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Slabicki, MikolajUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mock, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oakes, Christopher C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, ShihuiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oppermann, SinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lukas, MarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kim, VladislavUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sill, MartinUNSPECIFIEDorcid.org/0000-0001-7616-7665UNSPECIFIED
Benner, AxelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jauch, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sutton, Lesley AnnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Young, EmmaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rosenquist, RichardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liu, XiyangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jethwa, AlexanderUNSPECIFIEDorcid.org/0000-0003-3869-8662UNSPECIFIED
Lee, Kwang SeokUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lewis, JoeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Putzker, KerstinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lutz, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rossi, DavideUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mokhir, AndriyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oellerich, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zirlik, KatjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herling, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nguyen-Khac, FlorenceUNSPECIFIEDorcid.org/0000-0003-3107-6668UNSPECIFIED
Plass, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Andersson, EmmaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mustjoki, SatuUNSPECIFIEDorcid.org/0000-0002-0816-8241UNSPECIFIED
von Kalle, ChristofUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ho, Anthony D.UNSPECIFIEDorcid.org/0000-0002-1656-0833UNSPECIFIED
Hensel, ManfredUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Duerig, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ringshausen, IngoUNSPECIFIEDorcid.org/0000-0002-7247-311XUNSPECIFIED
Zapatka, MarcUNSPECIFIEDorcid.org/0000-0001-8287-5967UNSPECIFIED
Huber, WolfgangUNSPECIFIEDorcid.org/0000-0002-0474-2218UNSPECIFIED
Zenz, ThorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-199202
DOI: 10.1172/JCI93801
Journal or Publication Title: J. Clin. Invest.
Volume: 128
Number: 1
Page Range: S. 427 - 446
Date: 2018
Publisher: AMER SOC CLINICAL INVESTIGATION INC
Place of Publication: ANN ARBOR
ISSN: 1558-8238
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CHRONIC LYMPHOCYTIC-LEUKEMIA; DNA METHYLATION; TYROSINE KINASE; TARGETING BTK; B-CELLS; INHIBITOR; SENSITIVITY; MUTATIONS; IDENTIFICATION; IBRUTINIBMultiple languages
Medicine, Research & ExperimentalMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/19920

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item