New study explains why some types of melanoma resist targeted therapies

The most serious skin cancer is the world is cutaneous melanoma. In 2020, an estimated 325,000 new cases of melanoma were diagnosed and 57,000 people died from the disease.

But in new hope for melanoma patients, researchers have now pinpointed the mechanism behind one of the crafty ways melanoma cancer cells develop resistance to a targeted therapy – genomic deletions.

In genetics, a deletion is a mutation in which a part of a chromosome or sequence of DNA is left out during DNA replication, resulting in it disappearing.

The cancerous cells delete parts of the BRAF gene in response to treatment, altering the BRAF protein so that it lacks the regions targeted by BRAF inhibitor drugs.

Knowing that genomic deletions are the cause opens new avenues for developing therapies that could more effectively help patients with BRAF mutations.

Francisco Aya Moreno, an oncologist and recent PhD graduate at the Centre for Genomic Regulation (CGR) in Spain, says: “Melanoma drug resistance is a huge clinical problem because it occurs in almost all BRAF-mutated patients under BRAF/MEK inhibitor therapy and there are few or no therapeutic alternatives.

“There is an urgent need to understand the many different underlying mechanisms and find new strategies to deal with this constantly evolving arms race,” says Aya Moreno, who is lead author of the paper detailing the discovery in Cell Reports.

About half of all melanoma patients have tumours with mutations in the BRAF gene on chromosome 7, which helps control cell growth. However, when its mutated, as can occur in many different types of cancer, it instead can cause cells to grow and divide uncontrollably.

The discovery of BRAF mutations has led to development of targeted therapies to inhibit its function. Unfortunately about half of melanoma patients with BRAF mutations relapse within a year.

The new study found cancer cells create alternative versions of the BRAF protein (altBRAFs), which lack regions targeted by BRAF inhibitors, through genomic deletions.

“For years, we’ve known that some patients produce altBRAFs and these help the cancer resist treatment, but we misunderstood the mechanism behind their creation,” explains co-author Juan Valcárcel, Research Professor at the Catalan Institution for Research and Advanced Studies and researcher at CGR.

Surprisingly, the researchers found evidence of the same genomic deletions in melanomas which hadn’t been treated yet – meaning melanomas can naturally develop mechanisms that mimic drug resistance without exposure to drugs. Identifying and targeting these early resistance mechanisms through genetic testing before treatment begins could improve the efficacy of first-line therapies.

“There is an emerging class of drugs known as second generation RAF inibitors. Unlike BRAF inhibitors, these drugs have a broad spectrum, and so could potentially inhibit the function of altBRAFs,” adds Aya Moreno

“Clinical trials which are assessing their effectiveness should also expand to include melanoma patients with a normal functioning BRAF gene as well, and possibly to other cancer types which express altBRAFs.”

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