Melanoma tumours produce altBRAFs by genomic deletions

Source: Drug Target View, April 2024

Researchers at the Centre for Genomic Regulation (CRG) have discovered one of the mechanisms through which melanoma drug resistance occurs. Global incidences of the deadliest form of skin cancer are rising, meaning that more effective treatments are required.

About one in two melanoma patients will have mutations in the BRAF gene which cause the cells to divide uncontrollably. The discovery of BRAF mutations has led to development of targeted therapies to inhibit its function. In the last decade, a standard treatment option for melanoma has been to simultaneously target both BRAF mutations and MEK, two genes that are part of the MAPK signalling pathway. In cancer, this pathway is rewired for uncontrolled growth, so targeting two different critical points slows or stops cancer growth.

However, although the combined use of first-generation inhibitors prompt good initial responses, around 50 percent of melanoma patients with BRAF mutations will relapse within one year. Other mechanisms, which remain poorly understood, reactivate the MAPK pathway and cause this drug resistance. Dr Francisco Aya Moreno, oncologist and recent PhD graduate at the CRG, explained: “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.”