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The mitogen-activated protein kinase pathway in melanoma part I - Activation and primary resistance mechanisms to BRAF inhibition.
Journal article

The mitogen-activated protein kinase pathway in melanoma part I - Activation and primary resistance mechanisms to BRAF inhibition.

  • Amaral T Center for Dermatooncology, Department of Dermatology, University Hospital Tübingen, Liebermeisterstr. 25, 72076 Tübingen, Germany; Portuguese Air Force Health Direction, Paço do Lumiar, 1649-020 Lisbon, Portugal. Electronic address: teresa.amaral@med.uni-tuebingen.de.
  • Sinnberg T Center for Dermatooncology, Department of Dermatology, University Hospital Tübingen, Liebermeisterstr. 25, 72076 Tübingen, Germany.
  • Meier F Department of Dermatology, University Hospital Carl Gustav Carus, Technical University Dresden, Fetscherstr. 74D, 01307 Dresden, Germany.
  • Krepler C Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19104, USA.
  • Levesque M University of Zürich Hospital, Department of Dermatology, Wagistrasse 14, CH-8952 Schlieren, Zürich, Switzerland.
  • Niessner H Center for Dermatooncology, Department of Dermatology, University Hospital Tübingen, Liebermeisterstr. 25, 72076 Tübingen, Germany.
  • Garbe C Center for Dermatooncology, Department of Dermatology, University Hospital Tübingen, Liebermeisterstr. 25, 72076 Tübingen, Germany.
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  • 2017-02-08
Published in:
  • European journal of cancer (Oxford, England : 1990). - 2017
BRAF mutation
MAP kinase pathway
Metastatic melanoma
PI3K pathway
Primary resistance to targeted therapy
Antineoplastic Agents
Drug Resistance, Neoplasm
Humans
MAP Kinase Signaling System
Melanoma
Molecular Targeted Therapy
Mutation
Protein Kinase Inhibitors
Proto-Oncogene Proteins B-raf
English Mitogen-activated protein kinase (MAPK) pathway has an important role in normal cells and can be activated under physiological conditions. MAPK pathway activation is a fundamental step in several intracellular processes requiring a sequential phosphorylation of the different pathway components. In normal cells, when MAPK pathway activation occurs, it leads to cell growth and differentiation. In order to prevent persistent MAPK pathway activation, physiological upstream negative feedback also takes place. In cells harbouring BRAFV600 mutations, the process leading to MAPK pathway activation is different, and the negative physiological feedback does not exist thus leading to permanent MAPK pathway activation, which ultimately can lead to uncontrolled proliferation. Targeted therapy with rapidly accelerated fibrosarcoma - B (BRAF) and/or mitogen-activated extracellular signal-regulated kinase kinase (MEK) inhibitors is indicated in patients with metastatic melanoma harboring BRAFV600 mutations. However, several different resistance mechanisms to this therapy were identified. In this review, we focus on primary or intrinsic resistance mechanisms to BRAF and MEK inhibition. In this setting, although a BRAF mutation is identified, there is no response to treatment with either BRAF or MEK inhibitor.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/88410
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