Researchers have uncovered a previously unknown mechanism that helps melanoma cells spread through the body and evade some of the most effective cancer treatments available.
The findings, published in The EMBO Journal, reveal that a protein called nerve growth factor receptor (NGFR) has a central role in both tumour invasion and resistance to immunotherapy. In the longer term, this breakthrough could lead to much-needed new approaches to combat advanced disease.
Scientists at The Institute of Cancer Research, London, were part of the international collaboration that carried out the research, led by colleagues in Madrid, Spain. Funding for the contributing laboratory's work came from multiple organisations, including Breast Cancer Now, Cancer Research UK, Barts Charity, Worldwide Cancer Research, UK Research and Innovation, and The Institute of Cancer Research (ICR), which is both a research institute and a charity.
A significant discovery
Melanoma is the most serious form of skin cancer, with the potential to become life-threatening when it spreads beyond its original site. In recent years, immunotherapies have transformed treatment for many patients by helping the immune system recognise and attack cancer cells. However, not everyone benefits. Almost half of patients either fail to respond or eventually develop resistance to these therapies, leaving clinicians searching for new ways to overcome this challenge.
The new study suggests that NGFR could be a crucial part of the answer. NGFR activates a previously unrecognised pathway involving a protein called myosin light chain 2 (MLC2). This pathway appears to help melanoma cells become more invasive, allowing them to move through surrounding tissues and potentially spread to other parts of the body. At the same time, it contributes to the development of resistance to immunotherapy.
The discovery is particularly significant because it links two of the biggest challenges in melanoma treatment: preventing metastasis and maintaining the effectiveness of immunotherapy.
Experimental drug shows promise
The research remains at a preclinical stage, meaning that it has not yet been tested in patients. However, the team has reported encouraging results from laboratory and animal studies.
The scientists found that blocking NGFR with an experimental drug known as THX-B reduced the spread of melanoma and restored sensitivity to immunotherapy in models of the disease. In other words, tumours that had become resistant to treatment once again appeared vulnerable when NGFR activity was inhibited.
This suggests that by targeting the newly identified NGFR-to-myosin II signalling pathway, future therapies could potentially make existing immunotherapies more effective while also reducing the risk of cancer spread.
The findings could also open the door to more personalised treatment strategies. The study suggests that NGFR itself might eventually be used as a biomarker, helping doctors identify patients who are most likely to benefit from combination treatments involving both immunotherapy and NGFR-targeting drugs.
What the discovery could mean for patients
The immediate impact of the study is likely to be scientific rather than clinical. The findings provide researchers with a better understanding of why some melanomas stop responding to immunotherapy and offer a new area of investigation for future drug development. The work could also help guide additional laboratory studies and support the design of future clinical trials testing NGFR inhibitors alongside existing immune checkpoint therapies.
Over the longer term, the implications could be much more significant. It is possible that therapies targeting NGFR could help prevent melanoma from spreading, overcome resistance to immunotherapy and ultimately improve survival rates for patients with advanced disease.
The need for such treatments is substantial. Each year, about 17,000 people are diagnosed with melanoma in the UK and approximately 325,000 new cases are reported worldwide.
However, additional research must be carried out to make this patient impact a reality. The findings must first be confirmed through additional preclinical research. Following that, clinical trials will be needed to establish whether NGFR inhibitors are safe and effective in people. Scientists would also need to validate NGFR as a reliable biomarker before it could be used routinely in hospitals and cancer centres.
“A promising new avenue for future research”
Senior co-author Professor Victoria Sanz-Moreno, Professor of Cancer Cell and Metastasis Biology at the ICR, said:
“It was surprising that blocking a single receptor not only reduced the spread of melanoma but also appeared to restore the effectiveness of immunotherapy in resistant tumours. The discovery that NGFR controls resistance through the MLC2 pathway provides an unexpected new target for treating advanced melanoma.
“Despite years of progress in cancer research, much remains unknown about the biology of melanoma, so we are delighted that our findings offer a promising new avenue for future research.”
Senior and corresponding author Héctor Peinado, Associate Professor and Group Leader at CNB-CSIC, Madrid, said:
“Understanding precisely how tumours adapt and develop resistance is considered one of the most important challenges in oncology. By identifying a hidden mechanism that links cancer spread and treatment resistance, we have uncovered a potential vulnerability that could one day help more patients benefit from immunotherapy and live longer, healthier lives.”
Image credit: Bernd from Pixabay (modified)