In the fight against glioblastoma, scientists have discovered a cunning cellular Houdini that helps tumors evade treatment.
Imagine a molecular factory that produces a protein with no start, no end, and the ability to continuously generate cancer-sustaining signals. This isn't science fiction—it's the reality of a newly discovered mechanism called "rolling-translated EGFR" that's helping glioblastoma, the most aggressive brain cancer, resist treatment and thrive.
For decades, researchers have known that the epidermal growth factor receptor (EGFR) is overactive in over 50% of glioblastoma cases 1 3 . Traditional drugs designed to target EGFR have largely failed, leaving scientists puzzled about how the cancer continues to grow.
The discovery of rolling-translated EGFR reveals one of the tumor's secret weapons—and potentially, its Achilles' heel.
The most common mutant, EGFRvIII, lacks a critical external segment and fires continuously without an "off" switch . Despite knowing this, drugs targeting EGFR have shown disappointing results in clinical trials 1 8 . This mystery led researchers to dig deeper into how glioblastoma maintains its growth signals.
In 2021, researchers made a surprising discovery: a circular RNA version of the EGFR gene that produces a previously unknown protein variant through a process called "rolling translation" 2 5 .
Unlike typical linear RNA molecules that have clear start and end points, circular RNAs form continuous loops. These unusual structures were once considered genetic oddities, but are now recognized as important players in various biological processes, including cancer 5 .
The circular EGFR RNA (circ-EGFR) originates from the same gene as the standard EGFR receptor but skips the linear blueprint, creating a closed loop that behaves completely differently 5 .
Linear RNA
Circular RNA
The circular nature of circ-EGFR allows for a unique protein production process. Typically, ribosomes (cellular protein factories) read linear RNA blueprints from start to finish, then fall off. With circ-EGFR's continuous loop, the ribosome can circle around multiple times, generating a protein with repeating sequences 5 .
This process, dubbed "rolling translation," produces a novel protein complex that researchers termed rolling-translated EGFR (rtEGFR) 2 5 . Through a mechanism called "programmed -1 ribosomal frameshifting," the ribosome occasionally shifts reading frames, potentially bypassing stop signals that would normally halt production 5 . The result is a large, polymerized protein complex unlike any previously known EGFR variant.
To confirm the existence and function of rtEGFR, researchers designed a series of rigorous experiments 5 . Here's how they pieced together this complex puzzle:
Using advanced RNA sequencing techniques on samples from 97 glioblastoma patients, researchers first verified that circ-EGFR was present in tumors but barely detectable in normal brain tissue 5 . This specificity made it particularly interesting as a potential therapeutic target.
The team used specialized antibodies and liquid chromatography-tandem mass spectrometry to identify the protein products of circ-EGFR. These sophisticated tools allowed them to detect the unique rtEGFR protein and confirm it was different from any known EGFR variants 5 .
Through a series of cell culture and animal experiments, researchers discovered that rtEGFR doesn't act like a typical receptor. Instead, it partners with regular EGFR (including mutant forms like EGFRvIII), keeping them anchored at the cell membrane and preventing their natural degradation 5 . This constant membrane presence leads to sustained cancer-growing signals.
| Research Tool | Primary Function | Key Finding Enabled |
|---|---|---|
| RNA sequencing | Identify and quantify circular RNAs | Detected circ-EGFR in glioblastoma samples |
| Northern blot | Verify RNA structure and size | Confirmed circular nature of circ-EGFR |
| Liquid chromatography-tandem mass spectrometry | Identify and characterize proteins | Detected rtEGFR protein product |
| siRNA targeting circ-EGFR splice sites | Selectively block circ-EGFR production | Confirmed rtEGFR's role in tumor growth |
| Lentivirus-transfected cell lines | Stably alter gene expression in cells | Allowed functional tests of rtEGFR |
Table 1: Key Research Reagents and Their Functions in the rtEGFR Discovery
| Experimental Model | Intervention | Observed Outcome |
|---|---|---|
| Brain tumor-initiating cells (BTICs) | siRNA against circ-EGFR | Reduced self-renewal and tumorigenicity |
| Mouse xenograft models | rtEGFR deprivation | Enhanced efficacy of nimotuzumab treatment |
| Patient-derived tumor cells | rtEGFR blockade | Attenuated EGFR signaling and increased receptor degradation |
Table 2: Effects of rtEGFR Deprivation in Experimental Models
When researchers blocked rtEGFR production in brain tumor-initiating cells, they observed reduced tumor formation in mouse models and enhanced effectiveness of EGFR-targeting drugs like nimotuzumab 5 . This suggested that targeting rtEGFR could make existing treatments more effective.
The discovery of rtEGFR provides solutions to several longstanding questions in glioblastoma treatment resistance—and opens new therapeutic possibilities.
Because rtEGFR is largely absent from normal brain tissue but present in tumors, it represents a promising target for therapy 5 .
In the study of 97 glioblastoma patients, higher circ-EGFR levels correlated with poorer patient prognosis 5 .
| Parameter | Finding | Clinical Significance |
|---|---|---|
| circ-EGFR in tumor vs. normal tissue | Elevated in glioblastoma, low in normal brain | Potential therapeutic window for targeting rtEGFR |
| Correlation with EGFR signaling | Positive correlation with EGFR pathway activity | Indicates role in maintaining oncogenic signaling |
| Prognostic value | Higher levels predict poorer prognosis | Potential use as biomarker for disease stratification |
Table 3: Clinical Correlations of circ-EGFR in Glioblastoma Patients
The discovery of rtEGFR represents a paradigm shift in how we approach EGFR targeting in glioblastoma. Rather than relying exclusively on traditional inhibitors, researchers can now explore ways to:
The "shape-shifting" capabilities of cancer have long frustrated researchers, but each discovered mechanism like rolling translation provides new opportunities for smarter interventions. As we continue to unravel these complex processes, we move closer to effectively treating this devastating disease.
The journey from discovering a fundamental resistance mechanism to developing effective treatments remains challenging, but the rtEGFR story demonstrates that sometimes, solving old problems requires looking at them in a completely new way—or in this case, in circles.