Proliferation, differentiation and survival all hinge on the epidermal growth factor receptor (EGFR). Mismatches in EGFR signaling are involved in cancers, so they are easy targets for drugs. EGFR imaging is an oncology revolution now that researchers and clinicians can detect receptor expression, distribution and activity in real time. We dive into the why, how and why of EGFR imaging studies.

EGFR and Cancer: What Can Be Done with EGFR to Stop Cancer

EGFR is an ErbB transmembrane receptor tyrosine kinase. By binding ligands (eg, epidermal growth factor) to its extracellular structure, EGFR is 'turned on' and the receptor dimes and autophosphorylates its intracellular tyrosines. That signalling fades downstream cascades such as the PI3K-Akt, Ras-Raf-MEK-ERK cascades, that regulate most functions of the cell.

Such cancers as NSCLC, colourectal cancer and glioblastoma are caused by overexpression, mutation or amplification of EGFR. EGFR, then, became one of many targets for a targeted therapy like tyrosine kinase inhibitors (TKIs) or monoclonal antibodies (mAbs).

Figure 1. EGFR structure–function relationships at the plasma membrane. (Martin-Fernandez ML. 2022)

EGFR Imaging: The Cure or the Killer?

The older techniques for studying EGFR (immunohistochemistry, Western blotting, etc.) are informative but are static, endpoint-based. Imaging allows us to image live cells, tissues and animal models with dynamic, non-invasive visualization of EGFR that is critical to both receptor regulation and drug signalling.

Identifying Target Expression

Preclinical and clinical confirmation of target expression is a common use of EGFR imaging. The higher EGFR expression, the better responsive they are to EGFR-targeted therapies. With imaging, we can accurately measure receptor density to better stratify patients in clinical trials and avoid treatment failure.

Assessing Drug-Receptor Interaction

EGFR imaging is the direct measure of how the drug works with its targets. Imaging can show, for example, EGFR binding affinity, internalization and degradation upon drug binding. Such data are essential for designing and prescribing drugs at the highest level.

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Monitoring Therapeutic Efficacy

Capturing EGFR dynamics in the treatment room is a tool for monitoring the impact of therapies. Modifications in receptor expression, localisation or signalling activity can be markers of response or refractory to treatment, and allow adjustments to treatment regimens.

Imaging Techniques for EGFR Analysis

Some cutting-edge imaging methods are used to study EGFR in drug discovery, each with advantages and disadvantages.

Positron Emission Tomography (PET)

EGFR is commonly diagnosed by PET scan because it's sensitive and quantitative. Radiolabelled ligands or antibodies ([11C]-erlotinib, [89Zr]-labeled cetuximab) attach directly to EGFR and can be used to visualize receptor expression and drug-target dynamics in vivo. PET scans can especially be useful for screening patients with potential for EGFR targeted therapy and evaluating treatment response.

Fluorescence Imaging

Fluorescent antibodies, peptides or molecules bind to EGFR to fluoresce. You can also see the activity of receptors at subcellular level via confocal and live-cell imaging. Other quantifications of receptor dimerisation and signalling are possible with fluorescence resonance energy transfer (FRET) and fluorescence lifetime imaging microscopy (FLIM).

Magnetic Resonance Imaging (MRI)

MRI with high spatial resolution and tissue contrast can also image EGFR in large tissue or in animals. Anti-chemistry molecules linked to EGFR-binding molecules facilitate receptor imaging. It's anatomical and receptor mapping MRI (less sensitive than PET or fluorescence).

Optical Coherence Tomography (OCT)

OCT, or non-invasive CT, produces ultra-high resolution cross-sectional pictures of the tissues. In combination with EGFR-targeting contrast agents, OCT can be used to measure receptor expression in surface tissue (like the skin or the mucosa) and therefore has special applications for some cancers.

Drug Development and EGFR Imaging Applications

Integration of EGFR imaging into drug development pipelines has changed many aspects of oncology research and treatment.

Preclinical Drug Screening

EGFR imaging allows for the screening of candidate molecules at high throughput in the early drug development phase. If you can see how the receptors bound and communicated, you can see which compounds are effective and selective. Also image reveals off-target effects, enhances drug safety reports.

Patient Selection and Stratification

That's one of the problems with targeted therapy – finding patients who can be helped. EGFR imaging biomarkers — for example, tumor absorption of radiolabelled drugs — allow non-invasive patient categorisation. Imaging can show us tumors with high levels of EGFR expression or mutations so we can deliver treatment to the most appropriate patient.

Understanding Resistance Mechanisms

Resistance to EGFR targeted therapies is a huge hurdle in cancer care. Reactions to receptor expression, mutation or other signalling pathways responsible for resistance can be detected by imaging. In NSCLC, for example, resistance to T790M mutation-inducible resistance has been studied with PET imaging, and used to guide next-generation TKIs.

Monitoring Disease Progression

Chronic imaging of EGFR in treatment is used to see the progression of the disease in real-time. When doctors see changes in receptor expression or activity, they can modify treatments to thwart tumour progression or resistance.

Combination Therapy Optimization

EGFR imaging is a goldmine for combination therapy planning and efficacy. If researchers monitor the effects of drugs on EGFR signalling and tumour microenvironment, they might find therapeutically efficacious combinations.

Challenges and Future Directions

For all its benefits, EGFR imaging also has some hurdles to overcome to be fully utilized for drug development.

Technical Limitations

Each imaging technique comes with inherent limitations (sensitivity, resolution, depth of penetration of tissues). Combining multiple techniques, like PET-MRI or multimodal fluorescence and OCT can circumvent these restrictions and offer all the information needed.

Standardization

Because there are no standardised procedures for imaging the EGFR, reproducibility and cross-study comparisons can be challenging. It is imperative that we create common imaging agents, parameters, and analysis protocols to spread.

Translation to Clinical Practice

Preclinical imaging research is promising but needs to be validated at the highest level. Clinical trials need to prove that EGFR imaging helps the patient with better treatment and at lower cost.

Integration with Omics Data

An integrated view of EGFR biology could be drawn from imaging data, genomics, transcriptomics and proteomics. This kind of coupling can help find new biomarkers, anticipate the effect of treatments, and identify new therapeutic targets.

Conclusion

EGFR imaging analysis has now become a must-have in the formulation of targeted cancer treatments. Insights into receptor dynamics that are non-invasive and available in real time allow us to better understand the biology of the EGFR and to move more quickly towards drug discovery and development. And as the technology advances and the combination with other modalities becomes more seamless, EGFR imaging will continue to revolutionise oncology research, allowing for better and more specific treatments for cancer patients. Current efforts to improve current obstacles and extend its use lay in wait for a day when imaging-based drug development will become the new norm, improving the lives of millions of patients around the world.

1. Martin-Fernandez ML. Fluorescence Imaging of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Resistance in Non-Small Cell Lung Cancer. Cancers (Basel). 2022, 14(3):686.

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