Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/13725
Title: FRAX597, a PAK1 inhibitor, synergistically reduces pancreatic cancer growth when combined with gemcitabine
Authors: Yeo, Dannel;He, Hong;Patel, Oneel;Lowy, Andrew M;Baldwin, Graham S;Nikfarjam, Mehrdad
Issue Date: 16-Jan-2016
Citation: BMC Cancer 2016; 16: 24
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.
URI: http://ahro.austin.org.au/austinjspui/handle/1/13725
DOI: 10.1186/s12885-016-2057-z
ORCID: 0000-0002-0944-8747
0000-0003-4866-276X
PubMed URL: http://www.ncbi.nlm.nih.gov/pubmed/26774265
Type: Journal Article
Subjects: Pancreatic Neoplasms
Deoxycytidine
Pyridones
Appears in Collections:Journal articles

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