PAK signalling drives acquired drug resistance to MAPK inhibitors in BRAF-mutant melanomas View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-10

AUTHORS

Hezhe Lu, Shujing Liu, Gao Zhang, Bin Wu, Yueyao Zhu, Dennie T. Frederick, Yi Hu, Wenqun Zhong, Sergio Randell, Norah Sadek, Wei Zhang, Gang Chen, Chaoran Cheng, Jingwen Zeng, Lawrence W. Wu, Jie Zhang, Xiaoming Liu, Wei Xu, Clemens Krepler, Katrin Sproesser, Min Xiao, Benchun Miao, Jianglan Liu, Claire D. Song, Jephrey Y. Liu, Giorgos C. Karakousis, Lynn M. Schuchter, Yiling Lu, Gordon Mills, Yusheng Cong, Jonathan Chernoff, Jun Guo, Genevieve M. Boland, Ryan J. Sullivan, Zhi Wei, Jeffrey Field, Ravi K. Amaravadi, Keith T. Flaherty, Meenhard Herlyn, Xiaowei Xu, Wei Guo

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. More... »

PAGES

133

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/nature24040

DOI

http://dx.doi.org/10.1038/nature24040

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1091924455

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/28953887


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