BRAF: A Two-Faced Janus

Abstract

Gain-of-function of V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF) is one of the most frequent oncogenic mutations in numerous cancers, including thyroid papillary carcinoma, melanoma, colon, and lung carcinomas, and to a lesser extent, ovarian and glioblastoma multiforme. This mutation aberrantly activates the mitogen-activated protein (MAP) kinase extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway, thereby eliciting metastatic processes. The relevance of BRAF mutations stems from its prognostic value and, equally important, from its relevant therapeutic utility as an actionable target for personalized treatment. Here, we discuss the double facets of BRAF. In particular, we argue the need to implement diagnostic molecular algorithms that are able to detect this biomarker in order to streamline and refine diagnostic and therapeutic decisions.

Cancer Stem Cells—Key Players in Tumor Relapse

“…Other proliferative pathways that rely on tyrosine-kinase function are related to the MAPK cascade. Mutations on proteins involved in such signaling mechanisms are key drivers of different types of tumor: B-Raf, N-Ras, K-Ras are found in melanoma, colorectal cancer, thyroid cancer and lung cancer, among others [151][152][153]. TKIs were developed in order to specifically inhibit the mutated proteins, i.e., vemurafenib is a small molecule specifically conceived in order to target the B-Raf V600E mutation [154].…”

Interstitial Deletions Generating Fusion Genes

“…Mutations in BRAF, most commonly the V600E mutation, have been found in many malignancies such as melanoma, colorectal cancer, thyroid carcinoma, non-small cell lung carcinoma, hairy cell leukemia, non-Hodgkin lymphoma, and adenocarcinoma of lung (214)(215)(216). The mutations play a fundamental role in cancer development.…”

“…The mutations play a fundamental role in cancer development. They constitutively activate BRAF resulting in an over-performing RAF-MEK-ERK signaling cascade, promotion of cell proliferation and survival, and inhibition of apoptosis (214)(215)(216). The identification and characterization of pathogenic BRAF mutations have led to the development of BRAF kinase inhibitors used to treat patients whose cancers carry this particular genetic abnormality (214,215,217,218).…”

Challenges with Approved Targeted Therapies against Recurrent Mutations in CLL: A Place for New Actionable Targets

“…The most frequent mutated gene is BRAF, detected in 2% of CLL cases [5,95,96]. Most of these mutations cluster around the kinase domain [97], but they are different to the typical V600E mutation seen in other malignancies [98]. In addition, other mutations in this pathway have been reported: upstream BRAF (KITLG, KIT, PTPN11, GNB1, NRAS and KRAS) and downstream BRAF (MAP2K1 alias Mek1 and MAP2K2 alias Mek2) [95].…”