Systematic Mapping of Kinase Addiction Combinations in Breast Cancer Cells by Integrating Drug Sensitivity and Selectivity Profiles
Research output: Contribution to journal › Journal article › Research › peer-review
Chemical perturbation screens offer the possibility to identify actionable sets of cancer-specific vulnerabilities. However, most inhibitors of kinases or other cancer targets result in polypharmacological effects, which complicate the identification of target dependencies directly from the drug-response phenotypes. In this study, we developed a chemical systems biology approach that integrates comprehensive drug sensitivity and selectivity profiling to provide functional insights into both single and multi-target oncogenic signal addictions. When applied to 21 breast cancer cell lines, perturbed with 40 kinase inhibitors, the subtype-specific addiction patterns clustered in agreement with patient-derived subtypes, while showing considerable variability between the heterogeneous breast cancers. Experimental validation of the top predictions revealed a number of co-dependencies between kinase targets that led to unexpected synergistic combinations between their inhibitors, such as dasatinib and axitinib in the triple-negative basal-like HCC1937 cell line.
Original language | English |
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Journal | Chemistry & Biology |
Volume | 22 |
Issue number | 8 |
Pages (from-to) | 1144-55 |
Number of pages | 12 |
ISSN | 2451-9448 |
DOIs | |
Publication status | Published - 20 Aug 2015 |
Externally published | Yes |
- Apoptosis/drug effects, Breast Neoplasms/drug therapy, Cell Line, Tumor, Cell Proliferation/drug effects, Computer Simulation, Drug Resistance, Neoplasm, Female, Humans, Protein Kinase Inhibitors/pharmacology, Systems Biology/methods
Research areas
ID: 199428342