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

2017; Nature Portfolio; Volume: 550; Issue: 7674 Linguagem: Inglês

10.1038/nature24040

1476-4687

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 Song, Jephrey Y. Liu, Giorgos C. Karakousis, Lynn M. Schuchter, Yiling Lu, Gordon B. Mills, Yu‐Sheng 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,

Cellular Mechanics and Interactions

BRAF-inhibition resistance in metastatic melanoma occurs through p21-activated kinase-mediated reactivation of ERK, whereas resistance to combined BRAF and MEK inhibition occurs through p21-activated kinase-mediated regulation of JNK and β-catenin phosphorylation, mTOR pathway activation and apoptosis inhibition in many patients. Melanomas have been shown to respond well to the inhibition of BRAF and MEK signalling, but in many cases the tumours become resistant. Multiple resistance mechanisms have been described, and Wei Guo and colleagues now add a new one to the list. They found that resistance to combinations of BRAF and MEK inhibitors can be acquired following activation of PAK signalling, which activates alternative signalling pathways that drive tumorigenesis. Accordingly, a PAK inhibitor can overcome resistance and may prove a new therapeutic avenue to treating melanomas. 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.