Melanoma ‘breaks’ genes to resist the action of drugs, according to the Genomics Center

A study by the Center for Genomic Regulation of Barcelona reveals the mechanism that explains how melanoma, which causes the majority of deaths from skin cancer, resists drug treatment and finds other ways to reactivate, such as ‘break’ parts of your BRAF gene.

This gene normally produces a protein that helps control cell growth but mutations cause cells to grow and divide uncontrollably in many different types of cancer, but especially melanoma.

The study is led by Francisco Aya Moreno and co-directed by Professor Juan Valcárcel from the Center for Genomic Regulation and Dr. Ana Arance from IDIBAPS (August Pi i Sunyer Biomedical Research Institute), with the collaboration of Núria López Bigas’ group at the Institute. of Biomedical Research of Barcelona.

The work is published this Friday in the journal Cell Reports, and explains one of the mechanisms used by melanoma to develop resistance to drugs.

Melanoma causes the majority of deaths from skin cancer and its incidence worldwide is increasing, so new and more effective treatments are needed.

An important advance driven by scientists in recent years is in the clinical use of genetic tests to search for specific mutations and use drugs aimed at these therapeutic targets, for a more personalized and effective treatment.

About one in two melanoma patients have mutations in the BRAF gene, according to researchers, indicating that this gene normally produces a protein that helps control cell growth, but the mutations cause cells to grow and divide uncontrollably. .

In the last ten years, the standard treatment for melanoma was to simultaneously attack BRAF and MEK mutations, two genes that are part of the MAPK signaling pathway that, in cancer, is reconfigured to drive uncontrolled growth.

A fifty% of melanoma patients with BRAF mutations relapse within a year and the cancer acquires drug resistance, in addition to finding other ways to reactivate the MAPK pathway through various mechanisms.

Dr. Francisco Aya Moreno, an oncologist who recently obtained his doctorate at the Center for Genomic Regulation of Barcelona (CRG), considers that ““resistance (to drugs) is a major clinical problem because it occurs in almost all patients with mutations in the BRAF gene on therapy with BRAF/MEK inhibitors.”.

“There are few, if any, therapeutic alternatives, so there is an urgent need to understand the different underlying mechanisms and find new strategies to address the evolution of the disease.“, Add.

The study published today in the journal Cell Reports indicates that melanomas ‘break’ parts of their BRAF gene, which helps the tumor create alternative versions of the protein (altBRAFs) that do not have regions that BRAF inhibitors target. , making drugs less effective.

This finding was made with various laboratory models and with tumor samples from patients, the CRB has reported.

ICREA research professor Juan Valcárcel, co-author of the study and CRG researcher, explains that “For years, we have known that some patients produce altBRAF and that these help cancer resist the action of drugs, but we did not understand the mechanism responsible.”

“Knowing that genomic deletions are the cause (of the creation of altBRAFs) opens new avenues to develop therapies that could more effectively help patients with BRAF mutations”considers.

It is hoped that the effectiveness of first-line therapies against melanoma can now be improved, for example, by identifying resistance mechanisms with genetic screening.

Furthermore, the study shows that genomic deletions could be a more widespread mechanism of oncogenesis and resistance than previously believed.

The study authors found evidence of genomic deletions in melanomas with a normally functioning BRAF gene, as well as in other types of cancer, such as non-small cell lung, breast, kidney and prostate cancers.

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