Oral Presentation 30th Lorne Cancer Conference 2018

DCLK1 is a novel driver of gastric tumourigenesis (#11)

Michael Buchert 1 , Shoukat Sterle 1 , Annalisa Carli 1 , Janson Tse 1 , Stefanie Fischer 1 , Matthias Ernst 1
  1. Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia

Gastric Cancer (GC) is among the most common cancers globally with a dismal 5-year survival of less than 28% and an urgent need for the identification of novel biomarkers and molecular targets. The serine/threonine kinase doublecortin-like kinase 1 (DCLK1) has gained a lot of attention recently as a frequently mutated gene and novel prognostic biomarker in human tumours including colorectal cancer and pancreatic cancer. DCLK1 gene amplification and somatic missense mutations are frequently observed (10%) in human primary GC and overall survival is reduced in patients with high DCLK1 expression. Yet the mechanism(s) how DCLK1 contributes to tumourigenesis are poorly understood. Our own studies have shown that overexpression of DCLK1 in human gastric cancer cell lines increases their migratory and invasive potential in vitro and promotes the growth of tumour xenografts in vivo by increasing the cellular composition of the tumour stroma, resulting in increased deposition of collagen. Importantly, blocking the kinase activity of DCLK1 with a DCLK1-specific small molecule inhibitor completely abrogates the increase in migration and invasion of gastric cancer cells. Moreover, Dclk1 expression increases in the gastric tumours of gp130F/F mutant mice, a well-established mouse model of intestinal-type gastric cancer, and tumour burden is reduced in gp130F/F mice homozygous for a hypomorph Dclk1 allele and after treatment with the DCLK1 inhibitor. Tumours from treated mice also have reduced collagen in the stroma. Together this data suggests that DCLK1 may act as a tumour promoter by increasing matrix stiffness and introduces blocking of its kinase activity as a potential novel therapeutic target.