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RAF-Inhibitoren

RAF inhibitors

  • Leitthema
  • Published:
Der Onkologe Aims and scope

Zusammenfassung

Hintergrund

Die Inhibition des RAF-MAPK-Signalwegs mittels BRAF-Inhibitoren (oder MEK-Inhibitoren) in Tumorerkrankungen wie dem Melanom, die durch BRAF-Mutation forciert werden, ist ein Paradebeispiel für zielgerichtete Therapie. Jedoch stellt die Resistenzentwicklung gegenüber diesen Inhibitoren ein wesentliches Problem dar.

Ziel

Die Autoren geben einen Überblick über den Signalweg, berichten über neueste Studien und Nebenwirkungen dieser Substanzklasse und diskutieren potenzielle Strategien zur Überwindung der Therapieresistenz.

Methoden

Der Beitrag basiert auf einer Recherche und Auswertung aktueller Literatur.

Ergebnisse

BRAF-Inhibitoren beim fortgeschrittenen malignen Melanom mit BRAF-Mutation sind seit 2011 als Monotherapie zugelassen. Diese zielgerichtete Therapie zeigt eine deutliche Verbesserung des progressionsfreien Überlebens und des Gesamtüberlebens. Dem erfolgreichen Einsatz der BRAF-Inhibitoren beim Melanom folgte in kurzer Abfolge auch ein Einsatz bei anderen Tumorerkrankungen mit Nachweis von BRAF-V600E-Mutation. Im Allgemeinen sind BRAF-Inhibitoren gut verträglich. Verschiedene BRAF-Inhibitoren weisen jedoch ein unterschiedliches Nebenwirkungsspektrum auf.

Schlussfolgerung

Kombinationstherapien mit MEK-Inhibitoren führen zu einem verbesserten Ansprechen und längerem Gesamtüberleben.

Abstract

Background

Inhibition of the Raf-mitogen-activated protein kinase (RAF-MAPK) pathway with BRAF (or MEK) inhibitors is highly effective as targeted therapy in tumors driven by BRAF mutations, such as melanomas; however, the development of resistance towards these inhibitors is a major problem.

Objective

This article gives an overview of this signaling pathway, reports on the latest studies and side effects of this class of substances and discusses potential strategies to overcome emergence of resistance.

Methods

This work is based on a review and an evaluation of the literature.

Results

BRAF inhibitors have been approved for monotherapy of advanced BRAF mutation-driven malignant melanoma since 2011. This targeted therapy has demonstrated significant improvements in progression-free and overall survival. The successful use of BRAF inhibitors in melanoma was recently followed by their application in other malignant diseases featuring the BRAF-V600E mutation. BRAF inhibitors are generally well tolerated. However, different BRAF inhibitors exhibit different toxicity profiles.

Conclusion

Combination therapies with MEK inhibitors can improve treatment response and overall survival.

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Authors and Affiliations

  1. Klinische Kooperationseinheit für Dermatoonkologie des Deutschen Krebsforschungszentrums (DKFZ) Heidelberg, Mannheim, Deutschland

    Jochen Utikal

  2. Klinische Kooperationseinheit Dermatoonkologie des DKFZ an der Klinik für Dermatologie, Venerologie und Allergologie und Exzellenzzentrum Dermatologie Mannheim des Landes Baden-Württemberg, Universitätsmedizin Mannheim, Ruprecht-Karls-Universität Heidelberg, Theodor-Kutzer-Ufer 1–3, 68135, Mannheim, Deutschland

    Jochen Utikal

  3. Institut für Molekulare Medizin und Zellforschung (IMMZ), Medizinische Fakultät, und Centre for Biological Signalling Studies, BIOSS, Albert-Ludwigs-Universität, Freiburg, Deutschland

    Tilman Brummer

  4. Comprehensive Cancer Centre Freiburg CCCF, Freiburg, Deutschland

    Tilman Brummer

  5. Deutsches Konsortium für Translationale Krebsforschung (DKTK) und Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Deutschland

    Tilman Brummer & Thorsten Zenz

  6. Molekulare Therapie in der Hämatologie and Onkologie, Nationales Centrum für Tumorerkrankungen und Deutsches Krebsforschungszentrum (DKFZ) Heidelberg, Heidelberg, Deutschland

    Thorsten Zenz

  7. Innere Medizin V, Universitätsklinikum Heidelberg, Heidelberg, Deutschland

    Thorsten Zenz

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Correspondence to Jochen Utikal.

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Interessenkonflikt

J. Utikal hat an Advisory Boards teilgenommen oder hat Reiseunterstützung erhalten von Amgen, BMS, GSK, LeoPharma, MSD, Novartis, Roche. T. Brummer erhielt Vortragshonorar von der Firma Actelion, Schweiz. T. Zenz gibt an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine von den Autoren durchgeführten Studien an Menschen oder Tieren.

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Utikal, J., Brummer, T. & Zenz, T. RAF-Inhibitoren. Onkologe 23, 639–644 (2017). https://doi.org/10.1007/s00761-017-0225-7

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