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Updated: Jul 9, 2026
Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays
Published on: September 19, 2018
Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell
Ultan McDermott1, Sreenath V Sharma, Lori Dowell
1Center for Molecular Therapeutics, Massachusetts General Hospital Cancer Center and Harvard Medical School, 149 13th Street, Charlestown, MA 02129, USA.
Abstract:
Kinase inhibitors constitute an important new class of cancer drugs, whose selective efficacy is largely determined by underlying tumor cell genetics. We established a high-throughput platform to profile 500 cell lines derived from diverse epithelial cancers for sensitivity to 14 kinase inhibitors. Most inhibitors were ineffective against unselected cell lines but exhibited dramatic cell killing of small nonoverlapping subsets. Cells with exquisite sensitivity to EGFR, HER2, MET, or BRAF kinase inhibitors were marked by activating mutations or amplification of the drug target. Although most cell lines recapitulated known tumor-associated genotypes, the screen revealed low-frequency drug-sensitizing genotypes in tumor types not previously associated with drug susceptibility. Furthermore, comparing drugs thought to target the same kinase revealed striking differences, predictive of clinical efficacy. Genetically defined cancer subsets, irrespective of tissue type, predict response to kinase inhibitors, and provide an important preclinical model to guide early clinical applications of novel targeted inhibitors.
Insights
This study profiled 500 cancer cell lines against 14 kinase inhibitors, finding that genetic profiles predict drug response. Genetically defined cancer subsets, not tissue type, guide targeted cancer therapy selection.
Area of Science:
- Oncology
- Pharmacogenomics
- Molecular Biology
Background:
- Kinase inhibitors represent a significant advancement in cancer therapy, with efficacy heavily reliant on tumor-specific genetic alterations.
- Understanding the genetic underpinnings of drug sensitivity is crucial for optimizing targeted cancer treatments.
Purpose of the Study:
- To establish a high-throughput platform for profiling cancer cell line sensitivity to kinase inhibitors.
- To identify specific genetic profiles associated with drug sensitivity across diverse cancer types.
- To evaluate the predictive value of genetic markers for kinase inhibitor efficacy.
Main Methods:
- A high-throughput screening platform was developed to test the sensitivity of 500 diverse epithelial cancer cell lines against 14 kinase inhibitors.
- Genomic analysis was performed to identify mutations and amplifications correlating with drug sensitivity.
- Comparative analysis of different kinase inhibitors targeting the same kinase was conducted.
Main Results:
- Most kinase inhibitors showed efficacy only in small, specific subsets of cell lines, highlighting the importance of genetic selection.
- Sensitivity to inhibitors targeting EGFR, HER2, MET, or BRAF was strongly correlated with activating mutations or amplification of the respective targets.
- Novel drug-sensitizing genotypes were identified in cancer types not previously associated with susceptibility to specific kinase inhibitors.
- Significant differences in efficacy were observed between drugs targeting the same kinase, correlating with clinical outcomes.
Conclusions:
- Genetically defined cancer subsets, independent of tumor tissue of origin, are key predictors of response to kinase inhibitors.
- This preclinical model is valuable for guiding the early clinical application of novel targeted cancer therapies.
- The findings underscore the critical role of tumor genetics in personalized cancer medicine and drug development.
