ABSTRACT
BRAF gene mutations can be found in approximately 50% of melanomas, but the most common BRAF mutation leads to substitution at residue 600 of the protein, from valine to glutamic acid. BRAFV600E occurs in up to 95% of all melanoma cases and can be successfully blocked by using a combination of BRAF- and MEK inhibitors. The wider availability of next-generation sequencing is revealing more non-V600 BRAF mutations, and the clinical implications of these mutations are widely unknown. In this review, we will discuss the biology of the MAPK pathway and the different types of BRAF mutations as well as their effect on MEK activation. Current literature will be reviewed including in vitro data, case reports and case series.
Subject(s)
Melanoma/genetics , Mutation/genetics , Proto-Oncogene Proteins B-raf/genetics , Skin Neoplasms/genetics , Humans , MAP Kinase Kinase Kinases/genetics , MAP Kinase Signaling System/genetics , MAP Kinase Signaling System/physiology , Neoplasm Proteins/genetics , Oncogene Proteins, Fusion/genetics , ras Proteins/geneticsABSTRACT
The treatment of melanoma, the most aggressive form of skin cancer, is being revolutionized by the development of personalized targeted therapy approaches. Mutant-selective BRAF inhibitors and MEK inhibitors have demonstrated impressive clinical results in molecularly selected patients. However, emerging understanding of the molecular heterogeneity of this disease and the identification of multiple mechanisms of resistance to targeted therapies strongly support the rationale for combinatorial approaches. In this review, we will discuss the preclinical and clinical studies that are testing leading hypotheses and emerging combinatorial strategies for the future.
Subject(s)
Melanoma/drug therapy , Skin Neoplasms/drug therapy , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Clinical Trials as Topic , Combined Modality Therapy , GTP Phosphohydrolases/genetics , Humans , Melanoma/genetics , Membrane Proteins/genetics , Molecular Targeted Therapy , Mutation , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins B-raf/genetics , Skin Neoplasms/geneticsABSTRACT
The ataxia telangiectasia-mutated (ATM) gene has been implicated as an early barrier to the growth and progression of incipient solid tumors. Here, we show that germ-line nullizygosity for the mouse Atm gene significantly increases the proliferative index, net growth rate and multiplicity of intestinal adenomas in two distinct models of familial colon cancer: Apc(Min/+) and Apc(1638N/+). These effects of Atm deficiency are quantitatively different from deficiency for either of the genomic stability genes Bloom's syndrome helicase or DNA ligase 4, and the effect of Atm loss on tumor multiplicity is largely independent of the effect of ionizing radiation. Furthermore, the loss of heterozygosity rates at the adenomatous polyposis coli (Apc) locus are unaffected by Atm loss. Taken together, these data implicate the Atm gene product as a barrier to dysplastic growth in the early stages of intestinal tumor progression, independent of its effects on genomic stability.
