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Front Oncol. 2015 Feb 13;5:31. doi: 10.3389/fonc.2015.00031. eCollection 2015.

Phenotype switching in melanoma: implications for progression and therapy.

Author information

1
Oncogenic Signaling and Growth Control Program, Research Division, Peter MacCallum Cancer Center , East Melbourne, VIC , Australia ; Sir Peter MacCallum Department of Oncology, The University of Melbourne , East Melbourne, VIC , Australia.
2
Oncogenic Signaling and Growth Control Program, Research Division, Peter MacCallum Cancer Center , East Melbourne, VIC , Australia ; Sir Peter MacCallum Department of Oncology, The University of Melbourne , East Melbourne, VIC , Australia ; Department of Pathology, The University of Melbourne , East Melbourne, VIC , Australia.
3
Sir Peter MacCallum Department of Oncology, The University of Melbourne , East Melbourne, VIC , Australia ; Metastasis Research Laboratory, Research Division, Peter MacCallum Cancer Center , East Melbourne, VIC , Australia.
4
Oncogenic Signaling and Growth Control Program, Research Division, Peter MacCallum Cancer Center , East Melbourne, VIC , Australia ; Sir Peter MacCallum Department of Oncology, The University of Melbourne , East Melbourne, VIC , Australia ; Department of Pathology, The University of Melbourne , East Melbourne, VIC , Australia ; Department of Medicine, St Vincent's Hospital, The University of Melbourne , East Melbourne, VIC , Australia.

Abstract

Epithelial-mesenchymal transition (EMT) is a key process associated with the progression of epithelial cancers to metastatic disease. In melanoma, a similar process of phenotype switching has been reported and EMT-related genes have been implicated in promotion to a metastatic state. This review examines recent research on the role of signaling pathways and transcription factors regulating EMT-like processes in melanoma and their association with response to therapy in patients, especially response to BRAF inhibition, which is initially effective but limited by development of resistance and subsequent progression. We highlight studies implicating specific roles of various receptor tyrosine kinases (RTKs) in advancing melanoma progression by conferring a proliferative advantage and through promoting invasive phenotypes and metastasis. We also review the current knowledge of the mechanisms underlying resistance to BRAF inhibition and the potential role of melanoma phenotype switching in this process. In particular, we discuss how these important new insights may significantly enhance our ability to predict patterns of melanoma progression during treatment, and may facilitate rational development of combination therapies in the future.

KEYWORDS:

BRAF inhibition; EMT; RTK signaling; melanoma; metastasis; phenotype switching; resistance

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