Identifying kinase dependency in cancer cells by integrating high-throughput drug screening and kinase inhibition data.

Abstract

MOTIVATION:

Targeted kinase inhibitors have dramatically improved cancer treatment, but kinase dependency for an individual patient or cancer cell can be challenging to predict. Kinase dependency does not always correspond with gene expression and mutation status. High-throughput drug screens are powerful tools for determining kinase dependency, but drug polypharmacology can make results difficult to interpret.

RESULTS:

We developed Kinase Addiction Ranker (KAR), an algorithm that integrates high-throughput drug screening data, comprehensive kinase inhibition data and gene expression profiles to identify kinase dependency in cancer cells. We applied KAR to predict kinase dependency of 21 lung cancer cell lines and 151 leukemia patient samples using published datasets. We experimentally validated KAR predictions of FGFR and MTOR dependence in lung cancer cell line H1581, showing synergistic reduction in proliferation after combining ponatinib and AZD8055.

AVAILABILITY AND IMPLEMENTATION:

KAR can be downloaded as a Python function or a MATLAB script along with example inputs and outputs at: http://tanlab.ucdenver.edu/KAR/.

CONTACT:

[email protected].

SUPPLEMENTARY INFORMATION:

Supplementary data are available at Bioinformatics online.

• Authors: Karen A Ryall, Jimin Shin, Minjae Yoo, Trista K Hinz, Jihye Kim, Jaewoo Kang, Lynn E Heasley, Aik Choon Tan
• Journal: Bioinformatics (Oxford, England) (Bioinformatics) Vol. 31 Issue 23 Pg. 3799-806 (Dec 01 2015) ISSN: 1367-4811 [Electronic] England
• PMID: 26206305 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: [email protected].

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• Protein Kinase Inhibitors
• MTOR protein, human
• Receptor, Fibroblast Growth Factor, Type 1
• TOR Serine-Threonine Kinases

Topics

• Algorithms
• Antineoplastic Agents (pharmacology)
• Biomarkers, Tumor (genetics)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, pathology)
• Cell Proliferation (drug effects)
• Drug Evaluation, Preclinical
• Drug Resistance, Neoplasm (genetics)
• Drug Synergism
• Gene Expression Profiling
• High-Throughput Screening Assays
• Humans
• Immunoblotting
• Leukemia (drug therapy, genetics, pathology)
• Lung Neoplasms (drug therapy, genetics, pathology)
• Mutation (genetics)
• Protein Kinase Inhibitors (pharmacology)
• Receptor, Fibroblast Growth Factor, Type 1 (antagonists & inhibitors, genetics)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, genetics)
• Tumor Cells, Cultured