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

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 -