title: FRAX597, a PAK1 inhibitor, synergistically reduces pancreatic cancer growth when combined with gemcitabine.
abstract: 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 HIF1α 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.
authors.affiliation: Department of Surgery, Austin Health, University of Melbourne, Heidelberg, VIC, Australia. yeod@student.unimelb.edu.au.
authors.forename: Dannel
authors.initials: D
authors.lastname: Yeo
authors.affiliation: Department of Surgery, Austin Health, University of Melbourne, Heidelberg, VIC, Australia. hong.he@unimelb.edu.au.
authors.forename: Hong
authors.initials: H
authors.lastname: He
authors.affiliation: Department of Surgery, Austin Health, University of Melbourne, Heidelberg, VIC, Australia. patelo@unimelb.edu.au.
authors.forename: Oneel
authors.initials: O
authors.lastname: Patel
authors.affiliation: Department of Surgery, Division of Surgical Oncology, University of California at San Diego, Moores Cancer, La Jolla, CA, USA. alowy@ucsd.edu.au.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Lowy
authors.affiliation: Department of Surgery, Austin Health, University of Melbourne, Heidelberg, VIC, Australia. grahamsb@unimelb.edu.au.
authors.forename: Graham S
authors.initials: GS
authors.lastname: Baldwin
authors.affiliation: Department of Surgery, Austin Health, University of Melbourne, Heidelberg, VIC, Australia. mehrdad.nikfarjam@gmail.com.
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Nikfarjam
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004357:Drug Synergism; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D010183:Pancreatic Ducts / Q000187:drug effects / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011728:Pyridones / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D000093542:Gemcitabine
chemical_list: C584676:FRAX597; D011728:Pyridones; D011743:Pyrimidines; D003841:Deoxycytidine; C515903:PAK1 protein, human; D054462:p21-Activated Kinases; D000093542:Gemcitabine