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Nature. 2017 Oct 5;550(7674):133-136. doi: 10.1038/nature24040. Epub 2017 Sep 27.

PAK signalling drives acquired drug resistance to MAPK inhibitors in BRAF-mutant melanomas.

Author information

1
Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
2
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
3
Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
4
Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114, USA.
5
Department of Biology, Drexel University, Philadelphia, Pennsylvania 19104, USA.
6
Department of Computer Science, New Jersey Institute of Technology, Newark, New Jersey 07102, USA.
7
Abramson Cancer Center and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
8
Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
9
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA.
10
Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou, China.
11
Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
12
Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing, 100036, China.
13
Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
14
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
15
Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

Abstract

Targeted BRAF inhibition (BRAFi) and combined BRAF and MEK inhibition (BRAFi and MEKi) therapies have markedly improved the clinical outcomes of patients with metastatic melanoma. Unfortunately, the efficacy of these treatments is often countered by the acquisition of drug resistance. Here we investigated the molecular mechanisms that underlie acquired resistance to BRAFi and to the combined therapy. Consistent with previous studies, we show that resistance to BRAFi is mediated by ERK pathway reactivation. Resistance to the combined therapy, however, is mediated by mechanisms independent of reactivation of ERK in many resistant cell lines and clinical samples. p21-activated kinases (PAKs) become activated in cells with acquired drug resistance and have a pivotal role in mediating resistance. Our screening, using a reverse-phase protein array, revealed distinct mechanisms by which PAKs mediate resistance to BRAFi and the combined therapy. In BRAFi-resistant cells, PAKs phosphorylate CRAF and MEK to reactivate ERK. In cells that are resistant to the combined therapy, PAKs regulate JNK and β-catenin phosphorylation and mTOR pathway activation, and inhibit apoptosis, thereby bypassing ERK. Together, our results provide insights into the molecular mechanisms underlying acquired drug resistance to current targeted therapies, and may help to direct novel drug development efforts to overcome acquired drug resistance.

PMID:
28953887
PMCID:
PMC5891348
DOI:
10.1038/nature24040
[Indexed for MEDLINE]
Free PMC Article

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