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

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 () and Wei Guo ()
Additional contact information
Hezhe Lu: University of Pennsylvania
Shujing Liu: Perelman School of Medicine, University of Pennsylvania
Gao Zhang: Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute
Bin Wu: University of Pennsylvania
Yueyao Zhu: University of Pennsylvania
Dennie T. Frederick: Massachusetts General Hospital Cancer Center
Yi Hu: Drexel University
Wenqun Zhong: University of Pennsylvania
Sergio Randell: Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute
Norah Sadek: Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute
Wei Zhang: University of Pennsylvania
Gang Chen: University of Pennsylvania
Chaoran Cheng: New Jersey Institute of Technology
Jingwen Zeng: University of Pennsylvania
Lawrence W. Wu: Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute
Jie Zhang: New Jersey Institute of Technology
Xiaoming Liu: Perelman School of Medicine, University of Pennsylvania
Wei Xu: Perelman School of Medicine, University of Pennsylvania
Clemens Krepler: Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute
Katrin Sproesser: Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute
Min Xiao: Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute
Benchun Miao: Massachusetts General Hospital Cancer Center
Jianglan Liu: Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute
Claire D. Song: University of Pennsylvania
Jephrey Y. Liu: Perelman School of Medicine, University of Pennsylvania
Giorgos C. Karakousis: Hospital of the University of Pennsylvania
Lynn M. Schuchter: Perelman School of Medicine, University of Pennsylvania
Yiling Lu: The University of Texas MD Anderson Cancer Center
Gordon Mills: The University of Texas MD Anderson Cancer Center
Yusheng Cong: Institute of Aging Research, Hangzhou Normal University School of Medicine
Jonathan Chernoff: Cancer Biology Program, Fox Chase Cancer Center
Jun Guo: Peking University Cancer Hospital and Institute
Genevieve M. Boland: Massachusetts General Hospital
Ryan J. Sullivan: Massachusetts General Hospital Cancer Center
Zhi Wei: New Jersey Institute of Technology
Jeffrey Field: Perelman School of Medicine, University of Pennsylvania
Ravi K. Amaravadi: Hospital of the University of Pennsylvania
Keith T. Flaherty: Massachusetts General Hospital Cancer Center
Meenhard Herlyn: Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute
Xiaowei Xu: Perelman School of Medicine, University of Pennsylvania
Wei Guo: University of Pennsylvania

Nature, 2017, vol. 550, issue 7674, 133-136

Abstract: 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.

Date: 2017
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DOI: 10.1038/nature24040

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