Resistance mechanisms to targeted therapy in BRAF-mutant melanoma - A mini review

• Published in: Biochimica et biophysica acta. General subjects Vol. 1865; no. 1; p. 129736
• Main Authors: Tangella, Lokeswari P., Clark, Michael E., Gray, Elin S.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2021
• Subjects: Acquired resistance; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; cancer therapy; combination drug therapy; disease resistance; drug resistance; Drug Resistance, Neoplasm; enzyme inhibition; genetic heterogeneity; genetic resistance; Humans; Intrinsic resistance; MAP Kinase Signaling System - drug effects; melanoma; Melanoma - drug therapy; Melanoma - genetics; Melanoma - metabolism; Metabolic reprogramming; mitogen-activated protein kinase; Molecular Targeted Therapy; mutants; Mutation - drug effects; neoplasm cells; non-specific serine/threonine protein kinase; phenotypic plasticity; precision medicine; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins B-raf - metabolism; resistance mechanisms; survival rate; Targeted therapy; Tumour adaptations; Tumour plasticity; Tumour adaptations; Intrinsic resistance; Acquired resistance; Metabolic reprogramming; Targeted therapy; Tumour plasticity
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2020.129736

The introduction of targeted therapies for the treatment of BRAF-mutant melanomas have improved survival rates in a significant proportion of patients. Nonetheless, the emergence of resistance to treatment remains inevitable in most patients. Here, we review known and emerging molecular mechanisms that underlay the development of resistance to MAPK inhibition in melanoma cells and the potential strategies to overcome these mechanisms. Multiple genetic and non-genetic mechanisms contribute to treatment failure, commonly leading to the reactivation of the MAPK pathway. A variety of resistance mechanisms are enabled by the underlying heterogeneity and plasticity of melanoma cells. Moreover, it has become apparent that resistance to targeted therapy is underpinned by early functional adaptations involving the rewiring of cell states and metabolic pathways. The evidence presented suggest that the use of a combinatorial treatment approach would delay the emergence of resistance and improve patient outcomes. •Review of known and emerging molecular mechanisms that underlay the development of resistance to MAPK inhibition.•Resistance to targeted therapy is underpinned by early adaptations such as rewiring of cell states and metabolic pathways.•Discussion of potential strategies to overcome these mechanisms.•The use of a combinatorial treatment approach would delay the emergence of resistance and improve patient outcomes.