PMID- 26774265
OWN - NLM
STAT- MEDLINE
DCOM- 20161005
LR  - 20231111
IS  - 1471-2407 (Electronic)
IS  - 1471-2407 (Linking)
VI  - 16
DP  - 2016 Jan 16
TI  - FRAX597, a PAK1 inhibitor, synergistically reduces pancreatic cancer growth when 
      combined with gemcitabine.
PG  - 24
LID - 10.1186/s12885-016-2057-z [doi]
LID - 24
AB  - BACKGROUND: Pancreatic ductal adenocarcinoma remains one of the most lethal of 
      all solid tumours. Treatment options are limited and gemcitabine-based 
      chemotherapy remains the standard of care. Although growing evidence shows that 
      p21-activated kinase 1 (PAK1) plays a crucial role in pancreatic cancer, its role 
      has not been fully elucidated. This study aimed to characterise the expression 
      and functional relevance of PAK1 in pancreatic cancer. METHODS: PAK1 expression 
      was measured in pancreatic cancer specimens by immunohistochemistry and in 
      pancreatic cancer cell lines by western blotting. The effect of inhibition of 
      PAK1 by either shRNA knock-down (KD), or by a selective inhibitor, FRAX597, alone 
      or in combination with gemcitabine, on cell proliferation and migration/invasion 
      was measured by thymidine uptake and Boyden chamber assays, respectively. The 
      effect on tumour growth and survival was assessed in orthotopic murine models. 
      RESULTS: PAK1 was expressed in all human pancreatic cancer samples tested, an7d 
      was upregulated in all pancreatic cancer cell lines tested. PAK1 KD inhibited 
      pancreatic cancer cell growth and survival, and increased sensitivity to 
      gemcitabine treatment. AKT activity and HIF1alpha expression were also inhibited. 
      FRAX597 inhibited pancreatic cancer cell proliferation, survival, and 
      migration/invasion. When combined with gemcitabine, FRAX597 synergistically 
      inhibited pancreatic cancer proliferation in vitro and inhibited tumour growth in 
      vivo. CONCLUSIONS: These results implicate PAK1 as a regulator of pancreatic 
      cancer cell growth and survival. Combination of a PAK1 inhibitor such as FRAX597 
      with cytotoxic chemotherapy deserves further study as a novel therapeutic 
      approach to pancreatic cancer treatment.
FAU - Yeo, Dannel
AU  - Yeo D
AD  - Department of Surgery, Austin Health, University of Melbourne, Heidelberg, VIC, 
      Australia. yeod@student.unimelb.edu.au.
FAU - He, Hong
AU  - He H
AD  - Department of Surgery, Austin Health, University of Melbourne, Heidelberg, VIC, 
      Australia. hong.he@unimelb.edu.au.
FAU - Patel, Oneel
AU  - Patel O
AD  - Department of Surgery, Austin Health, University of Melbourne, Heidelberg, VIC, 
      Australia. patelo@unimelb.edu.au.
FAU - Lowy, Andrew M
AU  - Lowy AM
AD  - Department of Surgery, Division of Surgical Oncology, University of California at 
      San Diego, Moores Cancer, La Jolla, CA, USA. alowy@ucsd.edu.au.
FAU - Baldwin, Graham S
AU  - Baldwin GS
AD  - Department of Surgery, Austin Health, University of Melbourne, Heidelberg, VIC, 
      Australia. grahamsb@unimelb.edu.au.
FAU - Nikfarjam, Mehrdad
AU  - Nikfarjam M
AD  - Department of Surgery, Austin Health, University of Melbourne, Heidelberg, VIC, 
      Australia. mehrdad.nikfarjam@gmail.com.
LA  - eng
GR  - R01 CA155620/CA/NCI NIH HHS/United States
GR  - CA155620-01/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20160116
PL  - England
TA  - BMC Cancer
JT  - BMC cancer
JID - 100967800
RN  - 0 (FRAX597)
RN  - 0 (Pyridones)
RN  - 0 (Pyrimidines)
RN  - 0W860991D6 (Deoxycytidine)
RN  - EC 2.7.11.1 (PAK1 protein, human)
RN  - EC 2.7.11.1 (p21-Activated Kinases)
RN  - 0 (Gemcitabine)
SB  - IM
MH  - Adenocarcinoma/*drug therapy/genetics/pathology
MH  - Animals
MH  - Cell Line, Tumor
MH  - Cell Movement/drug effects
MH  - Cell Proliferation/drug effects
MH  - Deoxycytidine/administration & dosage/analogs & derivatives
MH  - *Drug Synergism
MH  - Humans
MH  - Mice
MH  - Neoplasm Invasiveness/genetics/pathology
MH  - Pancreatic Ducts/drug effects/pathology
MH  - Pancreatic Neoplasms/*drug therapy/genetics/pathology
MH  - Pyridones/*administration & dosage
MH  - Pyrimidines/*administration & dosage
MH  - Xenograft Model Antitumor Assays
MH  - p21-Activated Kinases/antagonists & inhibitors/*genetics
MH  - Gemcitabine
PMC - PMC4715347
EDAT- 2016/01/18 06:00
MHDA- 2016/10/07 06:00
PMCR- 2016/01/16
CRDT- 2016/01/18 06:00
PHST- 2015/08/12 00:00 [received]
PHST- 2016/01/08 00:00 [accepted]
PHST- 2016/01/18 06:00 [entrez]
PHST- 2016/01/18 06:00 [pubmed]
PHST- 2016/10/07 06:00 [medline]
PHST- 2016/01/16 00:00 [pmc-release]
AID - 10.1186/s12885-016-2057-z [pii]
AID - 2057 [pii]
AID - 10.1186/s12885-016-2057-z [doi]
PST - epublish
SO  - BMC Cancer. 2016 Jan 16;16:24. doi: 10.1186/s12885-016-2057-z.