Drug-perturbation-based stratification of blood cancer
Open Access
- 11 December 2017
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 128 (1), 427-445
- https://doi.org/10.1172/jci93801
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.Keywords
Funding Information
- Heidelberg Center for Personalized Oncology (P-005, P-021, P-031)
- Helmholtz Virtual Institute (Understanding, overcoming resistance to apoptosis, therapy in leukemia)
- Helmholtz Initiative (iMed)
- European Union (FP7 projects Radiant, Systems Microscopy, Horizon 2020 project SOUND)
- Hairy Cell Leukemia Foundation (Hairy Cell Leukemia Foundation)
- ERANET Transcan-2 (GCH -CLL -143)
- Swedish Cancer Society (Swedish Cancer Society)
- Swedish Research Council (Swedish Research Council)
- Lion’s Cancer Research Foundation (Lion’s Cancer Research Foundation)
- Selander’s Foundation (Selander’s Foundation)
- BMBF eMed (Bundesministerium für Bildung und Forschung)
This publication has 67 references indexed in Scilit:
- OncogenicCSF3RMutations in Chronic Neutrophilic Leukemia and Atypical CMLNew England Journal of Medicine, 2013
- YM155 Induces EGFR Suppression in Pancreatic Cancer CellsPLOS ONE, 2012
- Systematic identification of genomic markers of drug sensitivity in cancer cellsNature, 2012
- The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivityNature, 2012
- Phase II Study of Dasatinib in Relapsed or Refractory Chronic Lymphocytic LeukemiaClinical Cancer Research, 2011
- Inhibition of Mutated, Activated BRAF in Metastatic MelanomaNew England Journal of Medicine, 2010
- IL-2 signaling prevents T cell anergy by inhibiting the expression of anergy-inducing genesMolecular Immunology, 2008
- Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitorsNature Biotechnology, 2007
- The NCI60 human tumour cell line anticancer drug screenNature Reviews Cancer, 2006
- The BTB-kelch Protein KLHL6 Is Involved in B-Lymphocyte Antigen Receptor Signaling and Germinal Center FormationMolecular and Cellular Biology, 2005