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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Agnieszka Szwajda
  • Prson Gautam
  • Leena Karhinen
  • Sawan Kumar Jha
  • Jani Saarela
  • Sushil Shakyawar
  • Laura Turunen
  • Bhagwan Yadav
  • Jing Tang
  • Wennerberg, Krister
  • Tero Aittokallio

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.

OriginalsprogEngelsk
TidsskriftChemistry & Biology
Vol/bind22
Udgave nummer8
Sider (fra-til)1144-55
Antal sider12
ISSN2451-9448
DOI
StatusUdgivet - 20 aug. 2015
Eksternt udgivetJa

ID: 199428342