PMID- 28953887
OWN - NLM
STAT- MEDLINE
DCOM- 20180227
LR  - 20211204
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 550
IP  - 7674
DP  - 2017 Oct 5
TI  - PAK signalling drives acquired drug resistance to MAPK inhibitors in BRAF-mutant 
      melanomas.
PG  - 133-136
LID - 10.1038/nature24040 [doi]
AB  - 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 beta-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.
FAU - Lu, Hezhe
AU  - Lu H
AD  - Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 
      19104, USA.
FAU - Liu, Shujing
AU  - Liu S
AD  - Department of Pathology and Laboratory Medicine, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
FAU - Zhang, Gao
AU  - Zhang G
AD  - Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The 
      Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
FAU - Bin Wu
AU  - Bin Wu
AD  - Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 
      19104, USA.
FAU - Zhu, Yueyao
AU  - Zhu Y
AD  - Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 
      19104, USA.
FAU - Frederick, Dennie T
AU  - Frederick DT
AD  - Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114, USA.
FAU - Hu, Yi
AU  - Hu Y
AD  - Department of Biology, Drexel University, Philadelphia, Pennsylvania 19104, USA.
FAU - Zhong, Wenqun
AU  - Zhong W
AD  - Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 
      19104, USA.
FAU - Randell, Sergio
AU  - Randell S
AD  - Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The 
      Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
FAU - Sadek, Norah
AU  - Sadek N
AD  - Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The 
      Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
FAU - Zhang, Wei
AU  - Zhang W
AD  - Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 
      19104, USA.
FAU - Chen, Gang
AU  - Chen G
AD  - Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 
      19104, USA.
FAU - Cheng, Chaoran
AU  - Cheng C
AD  - Department of Computer Science, New Jersey Institute of Technology, Newark, New 
      Jersey 07102, USA.
FAU - Zeng, Jingwen
AU  - Zeng J
AD  - Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 
      19104, USA.
FAU - Wu, Lawrence W
AU  - Wu LW
AD  - Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The 
      Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
FAU - Zhang, Jie
AU  - Zhang J
AD  - Department of Computer Science, New Jersey Institute of Technology, Newark, New 
      Jersey 07102, USA.
FAU - Liu, Xiaoming
AU  - Liu X
AD  - Department of Pathology and Laboratory Medicine, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
FAU - Xu, Wei
AU  - Xu W
AD  - Abramson Cancer Center and Department of Medicine, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
FAU - Krepler, Clemens
AU  - Krepler C
AD  - Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The 
      Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
FAU - Sproesser, Katrin
AU  - Sproesser K
AD  - Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The 
      Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
FAU - Xiao, Min
AU  - Xiao M
AD  - Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The 
      Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
FAU - Miao, Benchun
AU  - Miao B
AD  - Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114, USA.
FAU - Liu, Jianglan
AU  - Liu J
AD  - Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The 
      Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
FAU - Song, Claire D
AU  - Song CD
AD  - Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 
      19104, USA.
FAU - Liu, Jephrey Y
AU  - Liu JY
AD  - Abramson Cancer Center and Department of Medicine, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
FAU - Karakousis, Giorgos C
AU  - Karakousis GC
AD  - Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, 
      Pennsylvania 19104, USA.
FAU - Schuchter, Lynn M
AU  - Schuchter LM
AD  - Abramson Cancer Center and Department of Medicine, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
FAU - Lu, Yiling
AU  - Lu Y
AD  - Department of Systems Biology, The University of Texas MD Anderson Cancer Center, 
      Houston, Texas 77054, USA.
FAU - Mills, Gordon
AU  - Mills G
AD  - Department of Systems Biology, The University of Texas MD Anderson Cancer Center, 
      Houston, Texas 77054, USA.
FAU - Cong, Yusheng
AU  - Cong Y
AD  - Institute of Aging Research, Hangzhou Normal University School of Medicine, 
      Hangzhou, China.
FAU - Chernoff, Jonathan
AU  - Chernoff J
AD  - Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 
      19111, USA.
FAU - Guo, Jun
AU  - Guo J
AD  - Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and 
      Institute, Beijing, 100036, China.
FAU - Boland, Genevieve M
AU  - Boland GM
AD  - Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts 
      02114, USA.
FAU - Sullivan, Ryan J
AU  - Sullivan RJ
AD  - Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114, USA.
FAU - Wei, Zhi
AU  - Wei Z
AD  - Department of Computer Science, New Jersey Institute of Technology, Newark, New 
      Jersey 07102, USA.
FAU - Field, Jeffrey
AU  - Field J
AD  - Department of Systems Pharmacology and Translational Therapeutics, Perelman 
      School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, 
      USA.
FAU - Amaravadi, Ravi K
AU  - Amaravadi RK
AD  - Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, 
      Pennsylvania 19104, USA.
FAU - Flaherty, Keith T
AU  - Flaherty KT
AD  - Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114, USA.
FAU - Herlyn, Meenhard
AU  - Herlyn M
AD  - Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The 
      Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
FAU - Xu, Xiaowei
AU  - Xu X
AD  - Department of Pathology and Laboratory Medicine, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
AD  - Department of Dermatology, Perelman School of Medicine, University of 
      Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
FAU - Guo, Wei
AU  - Guo W
AD  - Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 
      19104, USA.
LA  - eng
GR  - P01 CA025874/CA/NCI NIH HHS/United States
GR  - CA142928/CA/NCI NIH HHS/United States
GR  - P30 CA010815/CA/NCI NIH HHS/United States
GR  - R01 HL134923/HL/NHLBI NIH HHS/United States
GR  - P01 CA114046/CA/NCI NIH HHS/United States
GR  - P50 CA174523/CA/NCI NIH HHS/United States
GR  - R01 GM085146/GM/NIGMS NIH HHS/United States
GR  - CA174523/CA/NCI NIH HHS/United States
GR  - CA025874/CA/NCI NIH HHS/United States
GR  - CA114046/CA/NCI NIH HHS/United States
GR  - U54 CA193417/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20170927
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (CTNNB1 protein, human)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (beta Catenin)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (BRAF protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-raf)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (p21-Activated Kinases)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
SB  - IM
EIN - Nature. 2019 Jan;565(7738):E4. PMID: 30532003
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Cell Line, Tumor
MH  - Drug Resistance, Neoplasm/*drug effects/genetics
MH  - Enzyme Activation/drug effects
MH  - Female
MH  - Humans
MH  - JNK Mitogen-Activated Protein Kinases/chemistry/metabolism
MH  - MAP Kinase Signaling System/drug effects
MH  - Melanoma/*drug therapy/enzymology/*genetics
MH  - Mice
MH  - Mitogen-Activated Protein Kinase Kinases/chemistry/metabolism
MH  - Mitogen-Activated Protein Kinases/*antagonists & inhibitors
MH  - *Mutation
MH  - Phosphorylation/drug effects
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Proto-Oncogene Proteins B-raf/*genetics
MH  - Proto-Oncogene Proteins c-raf/chemistry/metabolism
MH  - Signal Transduction/*drug effects
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - beta Catenin/chemistry/metabolism
MH  - p21-Activated Kinases/antagonists & inhibitors/genetics/*metabolism
PMC - PMC5891348
MID - NIHMS902008
COIS- The authors declare no conflict of interests.
EDAT- 2017/09/28 06:00
MHDA- 2018/02/28 06:00
PMCR- 2018/04/09
CRDT- 2017/09/28 06:00
PHST- 2015/10/22 00:00 [received]
PHST- 2017/08/24 00:00 [accepted]
PHST- 2017/09/28 06:00 [pubmed]
PHST- 2018/02/28 06:00 [medline]
PHST- 2017/09/28 06:00 [entrez]
PHST- 2018/04/09 00:00 [pmc-release]
AID - nature24040 [pii]
AID - 10.1038/nature24040 [doi]
PST - ppublish
SO  - Nature. 2017 Oct 5;550(7674):133-136. doi: 10.1038/nature24040. Epub 2017 Sep 27.