Format

Send to

Choose Destination
Chem Biol. 2015 Aug 20;22(8):1144-55. doi: 10.1016/j.chembiol.2015.06.021. Epub 2015 Jul 23.

Systematic Mapping of Kinase Addiction Combinations in Breast Cancer Cells by Integrating Drug Sensitivity and Selectivity Profiles.

Author information

1
Institute for Molecular Medicine Finland, FIMM, University of Helsinki, 00014 Helsinki, Finland.
2
Institute for Molecular Medicine Finland, FIMM, University of Helsinki, 00014 Helsinki, Finland. Electronic address: krister.wennerberg@fimm.fi.
3
Institute for Molecular Medicine Finland, FIMM, University of Helsinki, 00014 Helsinki, Finland. Electronic address: tero.aittokallio@fimm.fi.

Abstract

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.

PMID:
26211361
DOI:
10.1016/j.chembiol.2015.06.021
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center