MAPK pathway in melanoma part II-secondary and adaptive resistance mechanisms to BRAF inhibition.
BRAF mutation can be identified in about 45% of the patients with metastatic melanoma. In these patients, BRAF and MEK inhibitors are able to induce rapid responses and to prolong survival. However, a significant percentage of patients will develop resistance to targeted therapy and will have progressive disease. MAPK pathway is the most important pathway involved in BRAF/MEK inhibition resistance, particularly MAPK pathway reactivation. Resistance mechanisms can be classified as 1) primary or intrinsic characterised by no response to therapy, 2) secondary or acquired with MAPK pathway reactivation after a time of tumour regression and 3) as adaptive with initial response and early resistance. BRAF inhibition also alters the immune response. Several publications have described immune effects of BRAF inhibition in melanoma tumours, showing that combining targeted and immunotherapy can improve response, despite a possible cross-resistance. Here, we continue the review on resistance mechanisms to BRAF/MEK inhibition and focus on the secondary and adaptive mechanisms.
Center for Dermatooncology, Department of Dermatology, Liebermeisterstr. 25, University Hospital Tübingen, 72076 Tübingen, Germany; Portuguese Air Force Health Direction, Paço do Lumiar, 1649-020 Lisbon, Portugal. Electronic address: teresa.amaral@med.uni-tuebingen.de.
Teresa
T
Amaral
Center for Dermatooncology, Department of Dermatology, Liebermeisterstr. 25, University Hospital Tübingen, 72076 Tübingen, Germany.
Tobias
T
Sinnberg
Department of Dermatology, University Hospital Carl Gustav Carus, Technical University Dresden, Fetscherstr. 74D, 01307 Dresden, Germany.
Friedegund
F
Meier
Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19104, USA.
Clemens
C
Krepler
University of Zürich Hospital, Department of Dermatology, Wagistrasse 14, Schlieren, CH-8952 Zürich, Switzerland.
Mitchell
M
Levesque
Center for Dermatooncology, Department of Dermatology, Liebermeisterstr. 25, University Hospital Tübingen, 72076 Tübingen, Germany.
Heike
H
Niessner
Center for Dermatooncology, Department of Dermatology, Liebermeisterstr. 25, University Hospital Tübingen, 72076 Tübingen, Germany.
Claus
C
Garbe
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000556:secondary; D058990:Molecular Targeted Therapy / Q000379:methods*; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf
BRAF mutation; Immune effects of BRAF inhibition; MAP kinase pathway; Metastatic melanoma; Secondary and adaptive resistance