EGFR suppression and drug-induced potentiation are widespread features of oncogenic RTK fusions

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Methods for Evaluating the Role of c-Fos and Dusp1 in Oncogene Dependence

Methods for Evaluating the Role of c-Fos and Dusp1 in Oncogene Dependence

Published on: January 7, 2019

Yuzhi Carol Gao, David Gonzalez-Martinez, Sofia Wissert

Biorxiv : the Preprint Server for Biology

|December 3, 2025

Abstract:

Regulation of cancer cells by their environment contributes to tumorigenesis and drug response, though the extent to which the oncogenic state can alter a cell's perception of its environment is not clear. Prior studies found that EML4-ALK, a receptor tyrosine kinase (RTK) fusion oncoprotein, suppresses transmembrane receptor signaling through EGFR. Moreover, suppression was reversed with targeted ALK inhibition, thereby promoting survival and drug tolerance. Here we tested whether such modulation of EGFR was common among other RTK fusions, which collectively are found in ∼5% of all cancers. Using live- and fixed-cell microscopy in isogenic and patient-derived cell lines, we found that a wide variety of RTK fusions suppress transmembrane EGFR and sequester essential adaptor proteins in the cytoplasm, as evidenced by the localization of endogenous Grb2. Targeted therapies rapidly released Grb2 from sequestration and potentiated EGFR. Synthetic optogenetic analogs of RTK fusions confirmed that cytoplasmic sequestration of Grb2 was sufficient to suppress perception of extracellular EGF and could do so without driving signaling from the synthetic fusion itself, demonstrating that fusion signaling and suppression of EGFR could be functionally decoupled. Our study uncovers that a large number of RTK fusions simultaneously act as both activators and suppressors of signaling, the mechanisms of which could be exploited for new biomimetic therapies that enhance cell killing and suppress drug tolerance.

Insights

Many receptor tyrosine kinase (RTK) fusions suppress EGFR signaling by sequestering proteins, impacting cancer drug response. This dual action offers potential for novel cancer therapies.

Area of Science:

Oncology
Molecular Biology
Cell Signaling

Background:

Cancer cells' environment influences tumorigenesis and drug response.
Receptor tyrosine kinase (RTK) fusions are oncogenic drivers in approximately 5% of human cancers.
Previous research indicated EML4-ALK fusion oncoproteins suppress epidermal growth factor receptor (EGFR) signaling.

Purpose of the Study:

To investigate if various RTK fusions commonly suppress EGFR signaling.
To understand the mechanisms by which RTK fusions modulate cell environment perception.
To explore therapeutic strategies targeting this dual signaling role.

Main Methods:

Utilized live- and fixed-cell microscopy in isogenic and patient-derived cell lines.
Assessed the localization of endogenous Grb2 to determine adaptor protein sequestration.
Employed synthetic optogenetic analogs of RTK fusions to decouple signaling functions.

Main Results:

A broad range of RTK fusions were found to suppress transmembrane EGFR signaling.
RTK fusions sequester essential adaptor proteins, such as Grb2, in the cytoplasm.
Targeted therapies reversed Grb2 sequestration, potentiating EGFR signaling and enhancing drug tolerance.
Optogenetic analogs confirmed cytoplasmic Grb2 sequestration sufficient to block EGF perception, independent of fusion signaling.

Conclusions:

RTK fusions exhibit a dual role, acting as both signaling activators and suppressors.
The suppression of EGFR signaling by RTK fusions is mediated by cytoplasmic sequestration of adaptor proteins.
These findings suggest potential for developing biomimetic therapies to improve cancer cell killing and overcome drug resistance.

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