3 years ago

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

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

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 resistance1,2,3,4,5,6. 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.

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

DOI: 10.1038/nature24040

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