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Updated: Jun 28, 2025
Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays
Published on: September 19, 2018
A heterogeneous pharmaco-transcriptomic landscape induced by targeting a single oncogenic kinase
Ross M Giglio1, Nicholas Hou2, Adeya Wyatt2
1Department of Molecular Pharmacology and Therapeutics, Columbia University Medical Center, New York, NY 10032, USA.
Abstract:
Over-activation of the epidermal growth factor receptor (EGFR) is a hallmark of glioblastoma. However, EGFR-targeted therapies have led to minimal clinical response. While delivery of EGFR inhibitors (EGFRis) to the brain constitutes a major challenge, how additional drug-specific features alter efficacy remains poorly understood. We apply highly multiplex single-cell chemical genomics to define the molecular response of glioblastoma to EGFRis. Using a deep generative framework, we identify shared and drug-specific transcriptional programs that group EGFRis into distinct molecular classes. We identify programs that differ by the chemical properties of EGFRis, including induction of adaptive transcription and modulation of immunogenic gene expression. Finally, we demonstrate that pro-immunogenic expression changes associated with a subset of tyrphostin family EGFRis increase the ability of cytotoxic T-cells to eradicate tumor cells. Our study provides a framework that considers each agent's unique and often unknown polypharmacology to prioritize compounds that induce clinically favorable molecular responses.
Insights
Epidermal growth factor receptor inhibitors show limited glioblastoma response. New research reveals drug-specific molecular programs that can enhance T-cell targeting of cancer cells.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Over-activation of the epidermal growth factor receptor (EGFR) is a key characteristic of glioblastoma, a deadly brain cancer.
- Despite this, EGFR-targeted therapies have yielded minimal clinical benefits, partly due to challenges in drug delivery to the brain and a poor understanding of drug-specific efficacy factors.
Purpose of the Study:
- To investigate the molecular responses of glioblastoma to epidermal growth factor receptor inhibitors (EGFRis) using advanced chemical genomics.
- To identify drug-specific features that influence the efficacy of EGFRis beyond brain penetration.
Main Methods:
- Utilized highly multiplex single-cell chemical genomics to analyze glioblastoma's response to various EGFRis.
- Employed a deep generative framework to decipher shared and drug-specific transcriptional programs induced by EGFRis.
Main Results:
- EGFRis were classified into distinct molecular groups based on their unique and shared transcriptional programs.
- Identified chemical property-dependent programs, including adaptive transcription and modulation of immunogenic gene expression.
- Demonstrated that certain tyrphostin family EGFRis induce pro-immunogenic changes, enhancing T-cell-mediated targeting of glioblastoma cells.
Conclusions:
- The study reveals distinct molecular classes of EGFRis based on their transcriptional effects in glioblastoma.
- Chemical properties of EGFRis significantly influence adaptive and immunogenic responses.
- Specific EGFRis can enhance glioblastoma's immunogenicity, offering a potential strategy to improve immunotherapy outcomes.
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