A major Breakthrough in understanding BRAF activation in cancer

This study opens up valuable perspectives for a better understanding resistance mechanisms to targeted therapies and for designing new therapeutic strategies against cancers carrying mutations in the BRAF protein.

Legend: Structural study of the BRAF kinase (blue) and oncogenic BRAF mutants (red) revealing the molecular basis of its uncontrolled activation.

BRAF adopts an autoinhibited structure, stabilized by the CRD domain and 14-3-3 proteins, enabling its regulation in healthy cells. Oncogenic BRAF mutants adopt a pre-active conformation taht promotes the proliferation of cancer cells.

A study led by Dr Marc Therrien, researcher at the Institute for Research in Immunology and Cancer (IRIC, Université de Montréal), in close collaboration with Dr Pierre Maisonneuve (CBMN/IECB - CNRS, Université de Bordeaux), has just been published in the prestigious journal Science.

The study reveals the molecular mechanisms by which oncogenic BRAF mutations bypass the cell's natural brakes, thereby activating a key signalling pathway involved in many cancers: the RAS-RAF-MEK-ERK pathway.

In a healthy cell, BRAF is maintained in an inactive state through the interaction of several regions of the protein and an essential partner: the 14-3-3 protein. This “lock” is released when an appropriate signal (the RAS protein) triggers activation of BRAF, which then organizes itself in an active state, where two copies of the BRAF protein assemble. While this activation mechanism is well known, how BRAF mutations - present in nearly 8% of human cancers - manage to break this lock in the absence of a signal remained unclear until now.

Using cryo-electron microscopy, the researchers visualized in 3D three classes of oncogenic BRAF mutations, including the most frequent one in oncology: BRAF V600E. Their work shows that these three classes of mutations share a common mode of activation : they destabilize the inactive conformation of BRAF and stabilize an intermediate conformation, called "pre-active", which closely resembles the active state, even in the absence of an activation signal.

Even more interestingly, the study shows that PLX8394 is able to correct this structural alteration by forcing the BRAF V600E mutated protein back into a resting state. This mechanism could explain the remarkable efficacy of PLX8394, currently in clinical development as a targeted treatment for several cancers harboring BRAF mutation.

 Reference : Hugo Lavoie et al., BRAF oncogenic mutants evade autoinhibition through a common mechanism. Science 388, eadp2742 (2025). DOI:10.1126/science.adp2742

Link to the CNRS Chemistry article: https://www.inc.cnrs.fr/fr/cnrsinfo/braf-le-verrou-moleculaire-que-les-cellules-cancereuses-peuvent-forcer