Rapid Resistance of FGFR-driven Gastric Cancers to Regorafenib and Targeted FGFR Inhibitors can be Overcome by Parallel Inhibition of MEK
David K Lau, Ian Y Luk, Laura J Jenkins, Andrew Martin, David S Williams, Kael L Schoffer, Fiona Chionh, Michael Buchert, Katrin Sjoquist, Alex Boussioutas, Sarah A Hayes, Matthias Ernst, Andrew J Weickhardt, Nick Pavlakis, Niall C Tebbutt, John M Mariadason
MOLECULAR CANCER THERAPEUTICS | AMER ASSOC CANCER RESEARCH | Published : 2021
Amplification or overexpression of the FGFR family of receptor tyrosine kinases occurs in a significant proportion of gastric cancers. Regorafenib is a multikinase inhibitor of angiogenic and oncogenic kinases, including FGFR, which showed activity in the randomized phase II INTEGRATE clinical trial in advanced gastric cancer. There are currently no biomarkers that predict response to this agent, and whether regorafenib is preferentially active in FGFR-driven cancers is unknown. Through screening 25 gastric cancer cell lines, we identified five cell lines that were exquisitely sensitive to regorafenib, four of which harbored amplification or overexpression of FGFR family members. These four ..View full abstract
Awarded by NHMRC
This project was supported by NHMRC project grant (1126094), an NHMRC Senior Research Fellowship (1046092 to J.M. Mariadason), an Innovation grant from the Australasian Gastrointestinal trial group, and the Operational Infrastructure Support Program, Victorian Government, Australia. D.K. Lau and L.J. Jenkins were supported by La Trobe University Australian Postgraduate Awards, and D.K. Lau received a scholarship from the RMA/Pancare Foundation. F. Chionh was supported by NHMRC Medical Postgraduate Scholarship (1017737). The INTEGRATE clinical trial was conducted by the Australasian Gastro-Intestinal Trials Group in collaboration with the National Health and Medical Research Council Clinical Trials Centre, University of Sydney.