BRAF-Mutated Colorectal Cancer: Clinical and Molecular Insights

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.

Contemporary treatment approaches for metastatic colorectal cancer driven by BRAF V600 mutations

“…Overactivation of the PI3K pathway was found in BRAF- mutant CRC cells mediating de novo resistance to BRAF inhibitors[ 33 , 37 , 38 ]. Besides, CRC cell lines with activating PIK3CA mutations or loss of PTEN expression were found to be more resistant to the growth-inhibiting effects of BRAF inhibitors compared to cell lines without these alterations[ 3 , 37 ].…”

“…A relatively small proportion (10%-15%) of patients with metastatic colorectal cancer (mCRC) have activating mutations in the BRAF gene[ 1 , 2 ]. The majority of these mutations involve exon 15 of the gene that encodes the activation loop within the kinase domain of BRAF protein, resulting in the substitution of valine at amino acid position 600 of the BRAF protein by a different amino acid, such as glutamate (V600E), aspartate (V600D), or lysine (V600K)[ 3 , 4 ]. These substitutions, especially V600E, which accounts for more than 90% of BRAF mutations in mCRC, can lead to an abnormal increase in the catalytic activity of the BRAF protein by inducing conformational changes in its activation loop[ 5 , 6 ].…”

BRAF Mutation in Colorectal Cancers: From Prognostic Marker to Targetable Mutation

“…BRAF-mutated CRC is currently receiving attention not only from clinicians, but also basic scientists, and thus numerous reviews have been published [3,[8][9][10][11][12][13][14][15][16]. As a medical oncology team, we would like to highlight BRAF-mutated CRC from the clinician's viewpoint.…”

Poly(3-hydroxybutyrate)/poly(amine)-coated nickel oxide nanoparticles for norfloxacin delivery: antibacterial and cytotoxicity efficiency

“…2 Colorectal cancer (CRC) is a heterogeneous disease and considered as one of the foremost reasons for mortality and morbidity in the world. 3 Various factors have been associated with the growth of colon cancer including mutation, bacterial infection and irradiation. It was predicted that several proteins of M. hominis may be targeted to the host cell ER, and possibly alter the normal pattern of protein folding.…”