- To provide an overview of the role of BRAF in different cancers
- To emphasize how the use of new clinical trial designs, new drugs and combination therapies are enabling studies of relevance of BRAF alterations in cancer patients
- To elaborate different precision medicine concepts emerging from the study of BRAF alterations in different tumour types
The BRAF gene encodes a serine/threonine protein kinase, which plays a role in regulating the MAPK/ERK signalling pathways, affecting cell growth and proliferation. Somatic mutations in BRAF gene have been found in different cancer types. The most common mutations in BRAF occur in codon 600. The mutation mimicks the phosphorylation of the kinase domain, causing a change in structure that favours a maintained active conformation.
BRAF mutations are frequent in melanoma, but are also present in a lower frequency in other tumours. Based on the functional relevance of the BRAF mutations, the effect on RAF dimerization and the sensitivity to BRAF or MEK inhibitors, a functional classification of BRAF mutations has been proposed.
In this module, the author, beyond elaborating BRAF mutations in melanoma and non-melanoma tumours and their therapeutic targeting, also tackles other molecular events affecting the BRAF gene.
Since BRAF inhibitors may only work in tumours with BRAF mutations, the development of BRAF inhibitors became a paradigm shift in drug development. A companion diagnostic was needed to enable the identification of patients who could benefit from treatment.
As BRAF alterations are present in many different tumour types, the author elaborates the efficacy of BRAF inhibitors across different cancers. Furthermore, he tackles the efficacy of BRAF inhibitors in settings with BRAF fusions or BRAF amplifications, as well as rare non-V600E mutations. At profound level, he elaborates inhibitors of the MAPK pathway, such as MEK inhibitors and their efficacy in such settings.
The author, fully committed to precision cancer medicine, discusses questions such as: Are all BRAF alterations equally tumourogenic? Are all drugs equally effective in diverse BRAF molecular settings? Is histology important, or is only the presence of an alteration in BRAF sufficient to predict a response to therapy?
The study of the role of BRAF alterations and their molecular biology and functional relevance, the use of MAPK inhibitors and the efficacy of combinations in different tumour types is quickly evolving, making this module an excellent overview of the BRAF targeting drugs landscape, new clinical trial designs and combination therapies research.
This E-Learning module was published in 2018 and expired in 2020.
The author has reported to be currently conducting research sponsored by Bayer Pharmaceuticals and Novartis. The author has also an Advisory Role with Novartis, Eli Lilly, Orion Pharma, SERVIER, MSD and Peptomyc.