Uncovering the potential culprits of melanoma treatment resistance

Researchers may have uncovered the mechanism behind the development of targeted therapy resistance in melanoma. According to a recent study published by Aya Moreno et al. cell report.

background

The global incidence of melanoma, the deadliest form of skin cancer, is increasing and new treatments are needed to reduce the health burden of this disease.

of BRAF Genes usually produce proteins that control cell growth. but, BRAF The mutation, which is present in about 50% of melanoma cases, can cause melanoma cells to grow and divide uncontrollably.Significant advances such as genetic testing to identify BRAF Mutations have enabled researchers to develop more targeted and personalized treatments that inhibit the function of these mutations.

For the past decade, one of the standard treatment options for melanoma patients has been to simultaneously target melanoma mutations. BRAF and Mech Genes that are part of the MAPK signaling pathway. In cancer, pathways can be rewired for uncontrolled cell proliferation. Targeting both of these mutations may help slow or stop cancer growth.

Despite good initial responses to first-generation BRAF/MEK inhibitor combinations, approximately 50% of patients BRAFMutated melanomas come back within a year. In such cases, melanoma cells may acquire treatment resistance and reactivate MAPK pathways through mechanisms that are not yet fully understood.

“Drug resistance in melanoma is a major clinical problem because it occurs in almost everyone. BRAF– Mutated patients receiving BRAF/MEK inhibitor therapy with little or no alternative treatment options. There is an urgent need to understand the various underlying mechanisms and find new strategies to deal with this ever-evolving arms race,” explained the study's lead author. Francisco Aya Moreno, MD, PhDa medically trained oncologist at the Genome Control Center in Barcelona.

Research methods and results

Researchers have discovered that melanoma cells destroy some of their cells in response to targeted therapy. BRAF Gene due to genomic deletion. As a result, tumors were able to produce an alternative version of the protein (altBRAF) that lacked the BRAF inhibitor's target region, reactivating the MAPK pathway and making the targeted therapy less effective. The results were consistent across different laboratory models and patient tumor samples.

The researchers noted that altBRAF was previously thought to be produced through alternative splicing, in which cells use the same gene to synthesize different proteins. The discovery that genomic deletions, rather than splicing, may be responsible for treatment resistance may call for a shift away from the use of drugs that target splicing as a therapeutic strategy.

“For many years we have known that some patients produce altBRAF and that these increase cancer treatment resistance, but we misunderstood the mechanisms behind their production. Genome “If we find that the deletion is the cause, we open new avenues to develop treatments that more effectively help patients.” BRAF mutations,” emphasized senior study author. Dr. Juan ValcarcelResearch Professor at the Institute of Advanced Study of Catalonia and researcher at the Center for Genome Regulation in Barcelona.

Remarkably, the researchers found evidence of the same genomic deletion in previously untreated melanoma cells, suggesting a mechanism by which melanoma mimics treatment resistance even in the absence of drug exposure. It was demonstrated that it is possible to develop naturally. The ability to identify and target these early resistance mechanisms through in-clinic genetic testing before treatment initiation could improve the efficacy of first-line treatments.

Further analysis reveals that genomic deletions may be a more widespread mechanism of carcinogenesis and treatment resistance than previously thought. Although still rare, researchers discovered altBRAF in normally functioning melanoma cells. BRAF It affects not only genes, but also other types of cancer, such as non-small cell lung cancer, breast cancer, renal cell cancer, and prostate cancer.

conclusion

Researchers hope their new findings will increase the number of patients who will benefit from targeted therapies in clinical development.

“A new class of drugs known as second-generation RAF inhibitors is emerging. Unlike BRAF inhibitors, these drugs are broadly acting and have the potential to inhibit altBRAF function. Clinical. test [that] The study needs to be expanded to include patients whose efficacy is being evaluated. [melanoma and] functioning properly BRAF Genes are similar and can also affect other types of cancer [that] altBRAF,” emphasized Dr. Aya Moreno. “Having the opportunity to approach this research with both a clinician's perspective and a scientist's curiosity was invaluable. It allowed us to not only understand how melanoma develops, but to I was able to do.” [cells] We discuss how this knowledge can lead to more effective treatments for patients, as well as patients who are resistant to treatment. “This fusion of clinical insight and scientific research is critical to making real progress in the fight against cancer,” he concluded.

Disclosure: For full study author disclosure, please visit: cell.com.