Melanoma is a deadly form of skin cancer, with incidence rates on the rise globally. New and effective treatments are needed to deal with the burden of the disease. Genetic tests are now being used by doctors to look for specific mutations that can be targeted for more personalized and effective treatment. Around half of melanoma patients have mutations in the BRAF gene, which can cause uncontrolled cell growth and division.
Over the last decade, targeting both BRAF mutations and MEK, two genes in the MAPK signaling pathway, has been a standard treatment for melanoma. This approach helps slow or stop cancer growth by targeting critical points in the pathway. However, around 50% of patients with BRAF mutations will relapse within a year due to the cancer developing resistance to the drugs. Understanding the mechanisms of drug resistance is crucial to finding new strategies to combat this problem.
A recent study published in Cell Reports has identified one way in which cancer cells develop resistance to targeted therapy. The study found that melanomas can ‘break’ parts of their BRAF gene, leading to the creation of alternative forms of the protein that are less affected by BRAF inhibitors. This allows the cancer to reactivate the MAPK pathway and render the drugs less effective. The discovery of this mechanism provides new insights into drug resistance in melanoma.
Researchers found evidence of genomic deletions in melanomas that had not been treated, suggesting that the cancer can naturally develop resistance mechanisms on its own. Targeting these early resistance mechanisms through genetic testing before treatment could improve the efficacy of therapies. The study also revealed that genomic deletions may be a more widespread mechanism of resistance in various types of cancer, suggesting potential new targets for therapy development.
The findings could lead to the development of new therapies that target altBRAFs more effectively, improving outcomes for patients with BRAF mutations. Clinical trials with second-generation RAF inhibitors, with a broader spectrum of action, may be expanded to include melanoma patients with normal functioning BRAF genes. This approach could benefit a broader population of patients with different types of cancer expressing altBRAFs.
The research, led by Dr. Francisco Aya Moreno and Professor Juan Valcarcel, highlights the potential of combining clinical insight with scientific investigation to improve cancer therapies. By understanding how melanomas develop resistance and identifying new targets for therapy, researchers hope to make progress in the fight against cancer. The study was a collaborative effort involving researchers from the Centre for Genomic Regulation, IDIBAPS, and IRB Barcelona.