Researchers may have uncovered the mechanisms behind the development of targeted therapy resistance in melanoma, according to a recent study published by Aya Moreno et al in Cell Reports.
Background
The global incidence of melanoma—the deadliest type of skin cancer—is rising, making novel treatments necessary to alleviate the health burden of the disease.
The BRAF gene normally creates a protein to control cell growth; however, BRAF mutations—which are present in about 50% of melanoma cases—can cause melanoma cells to grow and divide uncontrollably. Significant advances such as genetic tests to identify BRAF mutations have allowed researchers to develop more targeted and personalized therapies to inhibit the function of these mutations.
One of the standard treatment options for patients with melanoma over the past decade has been to simultaneously target mutations in the BRAF and MEK genes, which are part of the MAPK-signaling pathway. In cancer, the pathway can be rewired for uncontrolled cell growth. Targeting both of these mutations may help slow or stop cancer growth.
Despite positive initial responses to the combined use of first-generation BRAF/MEK inhibitors, approximately 50% of patients with BRAF-mutated melanoma will relapse within 1 year. In these cases, melanoma cells can acquire treatment resistance and reactivate the MAPK pathway through mechanisms that are still poorly understood.
“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,” explained lead study author Francisco Aya Moreno, MD, PhD, a medically trained oncologist at the Centre for Genomic Regulation in Barcelona.
Study Methods and Results
The researchers found that in response to targeted therapy, melanoma cells broke down parts of their BRAF gene through genomic deletions. As a result, the tumors were able to create alternative versions of the protein (altBRAFs) that lacked regions targeted by BRAF inhibitors, reactivate the MAPK pathway, and make targeted therapy less effective. The results were consistent across various lab models and patient tumor samples.
The researchers noted that altBRAFs were previously thought to be created through alternative splicing, in which cells use the same gene to synthesize different proteins. The discovery that genomic deletions, and not splicing, may be the cause behind treatment resistance could call for a shift away from the use of drugs targeting splicing as a therapeutic strategy.
"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. Knowing that genomic deletions are the cause opens new avenues for developing therapies that could more effectively help patients with BRAF mutations,” highlighted senior study author Juan Valcárcel, PhD, Research Professor at the Catalan Institution for Research and Advanced Studies and a researcher at the Centre for Genomic Regulation in Barcelona.
Notably, the researchers also found evidence of the same genomic deletions in melanoma cells that hadn’t been previously treated, demonstrating that melanoma could naturally develop mechanisms that mimic treatment resistance even without exposure to drugs. Identifying and targeting these early resistance mechanisms through genetic testing in a clinical setting prior to treatment initiation could improve the efficacy of first-line therapies.
Further analyses revealed that genomic deletions may be a more widespread mechanism of oncogenesis and treatment resistance than previously considered. Although still uncommon, the researchers discovered altBRAFs in melanoma cells with normal-functioning BRAF genes as well as in other types of cancers—including non–small cell lung cancer, breast cancer, renal cell carcinoma, and prostate cancer.
Conclusions
The researchers hope their new findings can increase the patient population benefiting from targeted therapies under clinical development.
“There is an emerging class of drugs known as second-generation RAF inhibitors. Unlike BRAF inhibitors, these drugs have a broad spectrum, and so could potentially inhibit the function of altBRAFs. Clinical trials [that] are assessing their effectiveness should also expand to include patients with [melanoma and] a normal functioning BRAF gene as well, and possibly to other cancer types [that] express altBRAFs,” underscored Dr. Aya Moreno. "Having the opportunity to approach this research with both a clinician’s perspective and a scientist’s curiosity has been invaluable. It allowed us to uncover not just how melanoma [cells] resist treatment but also how this knowledge could lead to more effective therapies for patients. This fusion of clinical insight and scientific investigation is crucial for making real progress in our fight against cancer,” he concluded.
Disclosure: For full disclosures of the study authors, visit cell.com.
