EGFR shows to be a promising therapeutic target in NF1 mutant melanoma

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Published: 6 May 2025
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Dr Milad Ibrahim - NYU Langone Health, New York, USA

Dr Milad Ibrahim speaks to ecancer about EGFR, a promising therapeutic target in NF1 mutant melanoma.

This study explores NF1 mutant melanoma, an aggressive subtype with limited treatment options.

Researchers classify melanoma into three subtypes and analyse patient-derived cell lines.

They find that EGFR is upregulated in NF1 mutant melanoma, and inhibiting EGFR causes cell death.

Existing drugs like Cetuximab show promise in reducing tumour growth in preclinical models, suggesting potential for clinical use and the need for further research on EGFR targeting in other cancers.

Dr Milad Ibrahim - NYU Langone Health, New York, USA

My study is about a subtype of melanoma. Melanoma is this type of skin cancer and genetically scientists have classified it into three distinct subtypes where mutations occur in specific genes, so BRAF mutant, NRAS mutant or NF1 mutant. My study focusses on NF1 mutant melanoma which is an aggressive subtype, it’s more aggressive than the other subtypes, yet it doesn’t have any treatments available, unlike the other subtypes.

So my study focussed on really understanding if there are some mechanisms or some targets that we can go after that can help us reduce the proliferation or treat this aggressive subtype. Unlike the other types of cancer where in BRAF or NRAS there is an activation in these genes, in NF1 it’s a loss mutation which means that NF1 is lost and therefore you cannot target NF1. You need to look for other targets that you can target so that you can decrease the cell proliferation of NF1.

What was the study design?

The study design is that over the past few years we have collected and established some cell lines isolated from melanoma patients. These cell lines were grown in culture and then we used these cell lines to do a comprehensive analysis – DNA sequencing, RNA sequencing, ATAC-seq, ChIP-seq – with the purpose of comparing the NF1 mutant to the NF1 wildtype and then doing some molecular studies and functional studies to test if these targets that we have identified functionally can be targeted and can be meaningful if we target them in treating cancer for these NF1 mutant patients.

What were the results of the study?

Our main finding is that we found that EGFR, which is epidermal growth factor receptor, is up-regulated in NF1 mutant melanoma. Now EGFR specifically is a target in many other cancers, however it’s not targeted in melanoma and there are a lot of drugs that are already established that can inhibit EGFR. So this finding, primarily we found that EGFR was over-expressed and we managed to validate this in other cohorts of melanoma, of NF1 mutant melanoma. We also have shown that these cells abandon EGFR signalling for them to signal and promote cell proliferation and growth. We also showed that when we knock down EGFR these cells don’t grow anymore, they die. Also we showed that by inhibition using drugs available, like cetuximab, which is a monoclonal antibody that targets EGFR, can inhibit these cells in vitro and they don’t affect the NF1 wildtype meaning they are selectively targeting NF1 mutant melanoma.

Then lastly what we did is that we tested this in pre-clinical models in in vivo mouse models and we found that both cetuximab and afatinib, which is a small molecule inhibitor of EGFR, overtured the proliferation of the NF1 mutant melanoma. So we think that it can have a clinical translation of our findings.

What is next for this study?

We propose that we can target EGFR in a subtype of melanoma that previously there was no targeted therapy available for these patients. I think that this is very important because if these patients have immunotherapy, which is the standard of care for all other melanoma patients, then they are left with no options and they can progress. Melanoma is a very metastatic, aggressive disease that can lead to death within months. So I think that this can at least bring some hope that there are targets, or EGFR can be targeted in this NF1 mutant melanoma.

Regarding the next steps, I think that our study actually does answer a question but it raises more questions of how do we position targeting EGFR in other types of cancer. EGFR is a monotherapy, we know that it will help the patient for a specific amount of time and then resistance will occur. It’s quite often used with combination therapies with EGFR. So I think there are a lot of questions to ask and that’s what we’re doing. We’re trying to see what other drugs we can combine with EGFR inhibition to be able to give these patients a more durable effect when we inhibit EGFR.