title: Akt Activation Mediates Acquired Resistance to Fibroblast Growth Factor Receptor Inhibitor BGJ398.
abstract: Activation of FGFR signaling through mutations, amplifications, or fusions involvingFGFR1, 2, 3, or4is seen in multiple tumors, including lung, bladder, and cholangiocarcinoma. Currently, several clinical trials are evaluating the role of novel FGFR inhibitors in solid tumors. As we move forward with FGFR inhibitors clinically, we anticipate the emergence of resistance with treatment. Consequently, we sought to study the mechanism(s) of acquired resistance to FGFR inhibitors using annotated cancer cell lines. We identified cancer cell lines that have activating mutations inFGFR1, 2, or3and treated them chronically with the selective FGFR inhibitor, BGJ398. We observed resistance to chronic BGJ398 exposure in DMS114 (small-cell lung cancer,FGFR1amplification) and RT112 (urothelial carcinoma,FGFR3fusion/amplification) cell lines based on viability assays. Reverse-phase protein array (RPPA) analysis showed increased phosphorylation of Akt (T308 and S473) and its downstream target GSK3 (S9 and S21) in both the resistant cell lines when compared with matching controls. Results of RPPA were confirmed using immunoblots. Consequently, the addition of an Akt inhibitor (GSK2141795) or siRNA was able to restore sensitivity to BGJ398 in resistant cell lines. These data suggest a role for Akt pathway in mediating acquired resistance to FGFR inhibition.Mol Cancer Ther; 16(4); 614-24. ©2017 AACR.
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Jharna
authors.initials: J
authors.lastname: Datta
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.|Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: Senthilkumar
authors.initials: S
authors.lastname: Damodaran
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Hannah
authors.initials: H
authors.lastname: Parks
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ocrainiciuc
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Jharna
authors.initials: J
authors.lastname: Miya
authors.affiliation: Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio.
authors.forename: Lianbo
authors.initials: L
authors.lastname: Yu
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Elijah P
authors.initials: EP
authors.lastname: Gardner
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Eric
authors.initials: E
authors.lastname: Samorodnitsky
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Michele R
authors.initials: MR
authors.lastname: Wing
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Darshna
authors.initials: D
authors.lastname: Bhatt
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.|Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: John
authors.initials: J
authors.lastname: Hays
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Julie W
authors.initials: JW
authors.lastname: Reeser
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio. sameek.roychowdhury@osumc.edu.|Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio.|Department of Pharmacology, The Ohio State University, Columbus, Ohio.
authors.forename: Sameek
authors.initials: S
authors.lastname: Roychowdhury
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics*; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D011743:Pyrimidines; C568950:infigratinib; C496348:FGFR1 protein, human; C496353:FGFR2 protein, human; C496365:FGFR3 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051498:Receptor, Fibroblast Growth Factor, Type 3; D051057:Proto-Oncogene Proteins c-akt