A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Systematic Mapping of Kinase Addiction Combinations in Breast Cancer Cells by Integrating Drug Sensitivity and Selectivity Profiles
Tekijät: Szwajda A, Gautam P, Karhinen L, Jha SK, Saarela J, Shakyawar S, Turunen L, Yadav B, Tang J, Wennerberg K, Aittokallio T
Kustantaja: CELL PRESS
Julkaisuvuosi: 2015
Journal: Chemistry and Biology
Tietokannassa oleva lehden nimi: CHEMISTRY & BIOLOGY
Lehden akronyymi: CHEM BIOL
Vuosikerta: 22
Numero: 8
Aloitussivu: 1144
Lopetussivu: 1155
Sivujen määrä: 12
ISSN: 1074-5521
DOI: https://doi.org/10.1016/j.chembiol.2015.06.021
Tiivistelmä
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.
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.
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