BioCentury
ARTICLE | Distillery Therapeutics

Therapeutics: Fibroblast growth factor receptor 1 (FGFR1; CD331); MAP kinase kinase 1 (MAP2K1; MEK1); MAP2K2 (MEK2); K-Ras (KRAS)

July 14, 2016 7:00 AM UTC

Studies in cell culture and mice suggest combining FGFR1 inhibitors with the MEK1/MEK2 inhibitor Mekinist trametinib could help treat KRAS-mutant lung and pancreatic cancers. In KRAS-mutant human lung and pancreatic cancer cell lines, Mekinist plus an shRNA targeting FGFR1 decreased proliferation synergistically compared with either agent alone. Also in the cell lines, Mekinist plus the FGFR1 inhibitors Iclusig ponatinib, infigratinib or AZD4547 decreased proliferation. In xenograft, patient-derived xenograft (PDX) and genetic mouse models of KRAS-mutant lung cancer, Mekinist combined with Iclusig or shRNA targeting FGFR1 decreased tumor growth compared with any of the agents alone. Next steps could include testing the combination of Mekinist and FGFR1 inhibitors in additional xenograft models of KRAS-mutant lung and pancreatic cancers.

Japan Tobacco Inc. and Novartis AG market Mekinist for melanoma with BRAF V600E or V600K mutations and have the compound in Phase II testing for KRAS-mutant non-small cell lung cancer (NSCLC), pancreatic cancer and solid tumors and earlier stages of development for other cancers. ...