TY - JOUR
T1 - Systematic Mapping of Kinase Addiction Combinations in Breast Cancer Cells by Integrating Drug Sensitivity and Selectivity Profiles
AU - Szwajda, Agnieszka
AU - Gautam, Prson
AU - Karhinen, Leena
AU - Jha, Sawan Kumar
AU - Saarela, Jani
AU - Shakyawar, Sushil
AU - Turunen, Laura
AU - Yadav, Bhagwan
AU - Tang, Jing
AU - Wennerberg, Krister
AU - Aittokallio, Tero
N1 - Copyright © 2015 Elsevier Ltd. All rights reserved.
PY - 2015/8/20
Y1 - 2015/8/20
N2 - Summary 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.
AB - Summary 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.
KW - Apoptosis/drug effects
KW - Breast Neoplasms/drug therapy
KW - Cell Line, Tumor
KW - Cell Proliferation/drug effects
KW - Computer Simulation
KW - Drug Resistance, Neoplasm
KW - Female
KW - Humans
KW - Protein Kinase Inhibitors/pharmacology
KW - Systems Biology/methods
U2 - 10.1016/j.chembiol.2015.06.021
DO - 10.1016/j.chembiol.2015.06.021
M3 - Journal article
C2 - 26211361
SN - 2451-9448
VL - 22
SP - 1144
EP - 1155
JO - Chemistry and Biology
JF - Chemistry and Biology
IS - 8
ER -
