Groundbreaking study reveals melanoma resistance strategy to targeted therapy

Melanoma is the most deadly skin cancer. With increasing incidence worldwide, new and more effective treatments are needed to reduce the health burden of this disease. An important advance in recent years is that doctors are using genetic testing to look for specific mutations that can be targeted for more personalized and effective treatments.

Approximately one in two melanoma patients has a mutation in the BRAF gene. This gene normally produces a protein that helps control cell growth, but mutations can cause cells to grow and divide uncontrollably, which is a contributing factor to many different types of cancer, including melanoma. occurs in

The discovery of BRAF mutations led to the development of targeted therapies to inhibit its function. One of the standard treatment options for melanoma over the past decade has been to target both BRAF mutations and MEK simultaneously. These two genes are part of the MAPK signaling pathway, and in cancer, this pathway is rewired to grow uncontrolled. Targeting two different critical points within the same domino chain can help slow or stop cancer growth.

Despite a good initial response to first-generation inhibitor combinations, approximately 50% of melanoma patients with BRAF mutations relapse within 1 year. Cancers acquire resistance to drugs and find other ways to respond to MAPK pathways through mechanisms that are still poorly understood.

Drug resistance in melanoma is a major clinical problem as it occurs in nearly all BRAF-mutant patients treated with BRAF/MEK inhibitors and there are few or no alternative treatments. There is an urgent need to understand the various underlying mechanisms and find new strategies to deal with this ever-evolving arms race. ”

Dr. Francisco Aya Moreno, a medically trained oncologist and recent PhD graduate at the Center for Genome Regulation (CRG) in Barcelona;

Research published today in the journal cell report elucidated one of the mechanisms by which cancer cells acquire resistance to targeted therapies. In this study, in response to treatment, melanoma It is possible to “break” part of the BRAF gene, also known as a genomic deletion. This helps tumors create an alternative version of the protein (altBRAF) that lacks the BRAF inhibitor's target region, reactivating the MAPK pathway and making the drug less effective. This finding was consistent across different models and patient tumor samples.

This finding is important because altBRAF was thought to be created through alternative splicing, when cells use the same gene to synthesize different proteins. The discovery that genomic deletions, rather than splicing, are the cause represents a shift from previous proposals to use splicing-targeting drugs as a therapeutic strategy.

“For many years we have known that some patients produce altBRAF and that these increase cancer treatment resistance, but we have misunderstood the mechanisms behind their production. “If we can identify the cause of this mutation, it opens up new avenues for developing treatments that can help patients more effectively.” Juan Valcarcel, an ICREA research professor, explains.

Remarkably, researchers found evidence of the same genomic deletion in melanomas that have not yet been treated. In other words, melanomas can naturally develop mechanisms that mimic drug resistance even when not exposed to drugs. Thorough genetic testing in the clinical setting before starting treatment may help identify and target these early resistance mechanisms to improve symptoms. efficacy of First-line therapy.

More surprisingly, further analysis revealed that genomic deletions may be a more widespread mechanism of carcinogenesis and resistance than previously thought. Although rare, researchers have found evidence of altBRAF in melanomas with normally functioning BRAF genes, as well as other types of cancer, including non-small cell lung cancer, breast cancer, kidney cancer, and prostate cancer. Did. This discovery could increase the number of patients who will benefit from targeted therapies currently in clinical development.

“There is an emerging class of drugs known as second-generation RAF inhibitors. Unlike BRAF inhibitors, these drugs are broadly acting and have the potential to inhibit altBRAF function. Clinical trials evaluating this need to be expanded to include patients with melanoma.'The normally functioning BRAF gene may also have an impact on other cancer types that express altBRAF.' Dr. Aya Moreno explains.

Dr. Aya Moreno is a member of the Center for Genome Regulation (CRG), the Institute for Biomedical Research (IRB Barcelona), the Augusto Pi Sunya Institute for Biomedical Research (IDIBAPS), and the Valdehebron Institute (VHIR), a medical Our goal is to use insights to drive research that benefits patients.

“Having the opportunity to approach this research with both a clinician's perspective and a scientist's curiosity was invaluable, allowing me to understand how melanoma resists treatment. Instead, we were able to uncover how this knowledge could lead to more effective treatments for patients. Insights and scientific research could help us truly advance the fight against cancer. It is extremely important,” concludes Dr. Aya Moreno.

The study was led by Dr. Aya Moreno and co-supervised by Professor Juan Valcarcel from the Center for Genome Regulation and Dr. Ana Arrans from IDIBAPS. The study was also carried out in collaboration with her Nuria López Bigas' research group at IRB Barcelona. Since completing his PhD at CRG, Dr. Ayamoreno has returned to the Medical Oncology Department at the Hospital Clinic of Barcelona.