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Review
. 2019 Oct 28;20(21):5369.
doi: 10.3390/ijms20215369.

BRAF-Mutated Colorectal Cancer: Clinical and Molecular Insights

Francesco Caputo  1 , Chiara Santini  2 , Camilla Bardasi  3 , Krisida Cerma  4 , Andrea Casadei-Gardini  5 , Andrea Spallanzani  6 , Kalliopi Andrikou  7 , Stefano Cascinu  8   9 , Fabio Gelsomino  10
Affiliations
Review

BRAF-Mutated Colorectal Cancer: Clinical and Molecular Insights

Francesco Caputo et al. Int J Mol Sci. .

Abstract

Colorectal cancer (CRC) is one of the leading causes of mortality and morbidity in the world. It is a heterogeneous disease, which can be classified into different subtypes, characterized by specific molecular and morphological alterations. In this context, BRAF mutations are found in about 10% of CRC patients and define a particular subtype, characterized by a dismal prognosis, with a median survival of less than 12 months. Chemotherapy plus bevacizumab is the current standard therapy in first-line treatment of BRAF-mutated metastatic CRC (mCRC), with triplet (FOLFOXIRI) plus bevacizumab as a valid option in patients with a good performance status. BRAF inhibitors are not so effective as compared to melanoma, because of various resistance mechanisms. However, the recently published results of the BEACON trial will establish a new standard of care in this setting. This review provides insights into the molecular underpinnings underlying the resistance to standard treatment of BRAF-mutated CRCs, with a focus on their molecular heterogeneity and on the research perspectives both from a translational and a clinical point of view.

Keywords: BRAF inhibitors; BRAF mutation; colorectal cancer; molecular targets; targeted therapy.

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Conflict of interest statement

The authors have no conflicts of interest to disclose.

Figures

Figure 1
Figure 1
Mitogen-activated protein kinase (MAPK) pathway in BRAF V600E-mutated metastatic colorectal cancer (mCRC). RAS activates the RAF family proteins (ARAF, BRAF, and CRAF). Activated RAF proteins lead to phosphorylation and activation of MEK1/2 proteins, which subsequently phosphorylate and activate ERKs, leading to cell growth.
Figure 2
Figure 2
Adaptive feedback signaling in BRAF V600E-mutated mCRC. (A) In BRAF V600E-mutated mCRC, activated BRAF V600E monomer activates the MAPK pathway (MEK and ERK), leading to cell growth. Activated ERK suppresses the upstream activation of MAPK pathway through negative feedback on TRK, such as EGFR. (B) BRAF inhibitors (iBRAF) lead to transient inhibition of MAPK pathway and loss of ERK-dependent negative feedback on RTK, resulting in paradoxical activation of MAPK pathway.
See this image and copyright information in PMC

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