Poster Presentation 27th Lorne Cancer Conference 2015

IDH1 mutation as a novel therapeutic target in cholangiocarcinoma (#195)

David Lau 1 , John Mariadason 1 , Andrew Weickhardt 1 2 , Niall Tebbutt 1 2
  1. Ludwig Institute for Cancer Research, Heidelberg, VIC, Australia
  2. Austin Health, Heidelberg, VIC, Australia

Background

Cancers of the biliary tract are rarely curable and few treatment options are available for advanced disease. Mutations of isocitrate dehydrogenase 1 (IDH1) have recently been discovered as a driver of oncogenesis in several cancers including glioma, leukaemia and cholangiocarcinoma[1]. Due to the scarcity of native cell lines, preclinical data supporting mutant IDH1 in biliary tract cancer as a therapeutic target is lacking. The study aim was to identify the IDH1 R132 mutation in a panel of biliary tract cell lines and assess its contribution to growth in vitro.

Methods

Sanger sequencing was performed on exon 4 IDH1 on a panel of 21 biliary tract cancer cell lines and was co-related with oncogenic 2-hydroxyglutarate (2HG) levels. The proliferation effects of IDH1 were explored with siRNA knockdown and AGI-5198, a specific inhibitor of mutant IDH1, using the MTS assay.

Results

An intrahepatic cell line was identified harbouring the IDH1 132C mutation. Whilst siRNA knockdown of IDH1 did not contribute to growth inhibition,

AGI-5198 caused growth inhibition of an IDH1 mutant cell line in comparison to IDH1 wild-type.

Conclusion

AGI-5198 causes growth inhibition in IDH1 mutation harbouring cell lines. This represents a novel therapeutic target in cholangiocarcinoma and further study into the mechanisms of action and combination therapeutic strategies is warranted.