An investigation has unraveled the systems behind how melanoma cancer cells develop resistance to treatment. The investigation discovered that, when exposed to certain medications, melanomas can “damage” parts of their BRAF gene, which is mutated in half of all melanomas. This enables the tumor to produce different versions of the protein that do not contain areas targeted by BRAF inhibitors, a key type of medication used to treat this cancer, reducing the effectiveness of the treatment. These findings open the door for alternative approaches to treating BRAF-mutated melanoma, which causes relapse in 50% of patients within a year.
MeMelanoma, a dangerous type of skin cancer, is on the rise globally. To combat this trend, doctors are turning to genetic tests to identify specific mutations that can be targeted for more personalized and effective treatment. For example, about half of melanoma patients have mutations in the BRAF gene, which can lead to uncontrolled cell growth. This genetic testing enables doctors to tailor treatment to the individual patient for better outcomes.The identification of BRAF mutations has resulted in the development of targeted therapies to block its activity. For the past decade, a common treatment approach for melanoma has been to target both BRAF mutations and MEK at the same time. These genes are part of the MAPK signaling pathway, which is reprogrammed for uncontrolled growth in cancer. By targeting two different critical points in this pathway, the growth of cancer can be slowed or stopped.
Although there have been positive initial responses to using the first-generation inhibitors together, about 50% of melanoma patients with BRAF mutations will experience a recurrence within a year. The cancer develops resistance to the treatment and resumes growing.Resistance to medications is a significant issue in the treatment of melanoma, particularly for patients with a BRAF mutation. Even with BRAF/MEK inhibitor therapy, drug resistance is almost guaranteed. This creates a need for a deeper understanding of the various mechanisms responsible for this resistance and for the development of new strategies to combat it. Dr. Francisco Aya Moreno, a medically-trained oncologist and recent PhD graduate at the Centre for Genomic Regulation (CRG) in Barcelona, emphasizes the urgency of this issue. The study published today aims to shed light on these mechanisms and explore potential new approaches to address this challenge.The medical journal Cell Reports has discovered the processes behind how cancer cells develop resistance to targeted therapy. The research revealed that when melanomas are treated, they can ‘break’ segments of their BRAF gene, which are known as genomic deletions. This allows the tumor to produce alternative forms of the protein (altBRAFs) that do not contain the regions targeted by BRAF inhibitors, reactivating the MAPK pathway and reducing the effectiveness of the drugs. This discovery was consistent across different laboratory models and samples from patient tumors.
These findings are significant because altBRAFs were previously thought to be produced through alternative splicing, which cells use the same gene to produce different proteins, a phenomenon known as alternative splicing. It has been discovered that genomic deletions, not splicing, are responsible for this, shifting away from previous proposals to target splicing with drugs as a therapeutic strategy.
“We have long been aware that some patients produce altBRAFs, which help cancer resist treatment, but the mechanism behind their creation was misunderstood. Understanding that genomic deletions are the cause opens up new possibilities for developing therapies that could more effectively aid patients with BRAF mutations,” explains ICREA Research Professor Juan Valcarcel., co-author of the study and researcher at the Centre for Genomic Regulation.
Interestingly, the study discovered evidence of identical genomic deletions in untreated melanomas. Essentially, melanomas can develop resistance to drugs on their own, without any exposure to the drugs. By identifying and targeting these early resistance mechanisms through comprehensive genetic testing before starting treatment, the effectiveness of initial therapies could be improved.
Furthermore, additional analyses showed that genomic deletions may be a more common mechanism of cancer development and proliferation.Researchers have discovered that there is more resistance to targeted treatments than previously believed. They have found evidence of altBRAFs in melanomas with a normally functioning BRAF gene, as well as in other types of cancer such as non-small cell lung cancer, breast cancer, kidney cancer, and prostate cancer. This could potentially expand the patient population that could benefit from targeted treatments that are currently being developed. There are also new drugs known as second generation RAF inhibitors that have a broader spectrum and could potentially inhibit the function of altBRAFs. Clinical trials are underway to assess their effectiveness.”Effectiveness should expand to encompass patients with melanoma who have a normal functioning BRAF gene, and potentially to other types of cancer that express altBRAFs,” states Dr. Aya Moreno.
Dr. Aya Moreno is part of the second cohort of the PhD4MD programme, a collaborative initiative between the Centre for Genomic Regulation (CRG), the Institute for Research in Biomedicine (IRB Barcelona), the August Pi i Sunyer Biomedical Research Institute (IDIBAPS), and the Vall d’Hebron Research Institute (VHIR). The program is designed to utilize the medical expertise of a doctor to advance research that benefits patients.
“Having the opportunity to approach this research with both medical and scientific perspectives is incredibly valuable,” Dr. Moreno adds.This research has been a valuable combination of a clinician’s perspective and a scientist’s curiosity. This approach has allowed us to not only understand how melanomas resist treatment, but also how this knowledge can lead to better therapies for patients. Dr. Aya Moreno concludes, “The fusion of clinical insight and scientific investigation is essential for making real progress in our battle against cancer.”
The study, led by Dr. Aya Moreno and co-supervised by Professor Juan Valcarcel at the Centre for Genomic Regulation and Dr. Ana Arance at IDIBAPS, was conducted in collaboration with Nuria López Bigas’ research group at IRB Barcelona. This collaborative effort has been crucial in advancing our understanding of melanoma treatment resistance.PhD Aya Moreno, now at CRG, has returned to the Medical Oncology department at Hospital Clinic in Barcelona.
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