Melanoma causes the most deaths Skin cancer. The global incidence continues to increase and new and more effective treatments are needed to ease the health burden of the disease. An important advance in recent years is the clinical use of Genetic testing to search for specific mutations and deploy drugs that target these therapeutic targets to provide more personalized and effective treatment.
Approximately every second melanoma patient has mutations in the melanoma BRAF gene. This gene normally produces a protein that helps control cell growth. However, mutations cause cells to grow and divide uncontrollably, which occurs in many different types of cancer, but particularly melanoma.
The discovery of BRAF mutations has led to the development of Therapies to inhibit its function. For the past decade, the standard treatment for melanoma has been to simultaneously target BRAF and MEK mutations. These two genes are part of the MAPK signaling pathway, which is reconfigured in cancer to drive uncontrolled growth. Targeting two different hotspots on the same molecular “domino chain” helps slow or stop cancer growth.
Despite an excellent initial response to the combined use of first-generation inhibitors, approximately 50% of melanoma patients with BRAF mutations experience relapse within 1 year. Cancer acquires Drug resistanceto find other ways to reactivate the MAPK signaling pathway through different mechanisms.
Resistance represents a major clinical problem as it occurs in almost all patients with BRAF mutations during treatment.
“Resistance is a major clinical problem because it occurs in almost all patients with BRAF mutations receiving therapy with BRAF/MEK inhibitors. There are few or no therapeutic alternatives. There is an urgent need to understand the various underlying mechanisms and find new strategies to address the constant evolution of the disease,” says Francisco Aya Morenoan oncologist who recently completed his PhD at the Center for Genomic Regulation (CRG) in Barcelona.
Changes for future therapeutic strategies
A study published today in the journal Cell Reports explains one of the mechanisms that melanomas use to develop resistance to drugs. In response to treatment, melanomas “break down” parts of their BRAF gene, also called a genomic deletion. This helps the tumor Create alternative versions of the protein (altBRAFs), which lack regions targeted by BRAF inhibitors, reactivating the MAPK pathway and making the drugs less effective. The finding was consistent across multiple laboratory models and patient tumor samples.
The results are important because altBRAFs were thought to be produced by Splice, a biological process that cells use to synthesize different proteins from the same gene. The discovery that genomic deletions and not the Spliceare the cause of the formation of altBRAFs, changes the focus of future therapeutic strategies.
Knowing that genomic deletions are the cause opens new avenues for the development of therapies
“We have known for years that some patients produce altBRAF and that these help the cancer resist the effects of drugs, but we did not understand the mechanism responsible. Knowing that genomic deletions are the cause opens new avenues for the development of therapies that could help more effectively for patients with BRAF mutations,” explains ICREA research professor Juan ValcarcelCo-author of the study and researcher at the Center for Genomic Regulation.
Surprisingly, the study found the same genomic deletions in melanomas that had not yet been treated with the drug combination. In other words, melanomas naturally develop mechanisms that mimic drug resistance, even without exposure to them. The finding allows us to improve the effectiveness of first-line therapies, for example by identifying these resistance mechanisms genetic studies.
Even more surprising, the study also shows that genomic deletions may be a more widespread mechanism of oncogenesis and resistance than previously thought. Although rare, the study authors found evidence of genomic deletions in melanomas with a normally functioning BRAF gene, as well as in other cancers including Lung cancer of non-small cells Breast cancerHe Kidney cancer and that Prostate cancer.
The opportunity to approach this research from the perspective of a physician-scientist was invaluable.
The findings could increase the proportion of patients who benefit from treatments which are currently in clinical development. “There is a new class of drugs known as second-generation RAF inhibitors. Unlike BRAF inhibitors, these drugs have a broad spectrum and therefore could inhibit the function of altBRAFs. Clinical trials to evaluate their effectiveness should also be expanded to include melanoma patients with a normally functioning BRAF gene and possibly other cancers that express altBRAFs,” explains Aya Moreno.
“The opportunity to approach this research from the perspective of a physician and a scientist was invaluable. This allowed us to discover not only how melanomas cause resistance to treatment, but also how this knowledge might lead to this.” most effective therapies for patients. “This combination of different findings is crucial to making real progress in the fight against cancer,” the researcher concludes.