title: Crosstalk between KIT and FGFR3 Promotes Gastrointestinal Stromal Tumor Cell Growth and Drug Resistance.
abstract: Kinase inhibitors such as imatinib have dramatically improved outcomes for patients with gastrointestinal stromal tumor (GIST), but many patients develop resistance to these treatments. Although in some patients this event corresponds with mutations in the GIST driver oncogenic kinase KIT, other patients develop resistance without KIT mutations. In this study, we address this patient subset in reporting a functional dependence of GIST on the FGF receptor FGFR3 and its crosstalk with KIT in GIST cells. Addition of the FGFR3 ligand FGF2 to GIST cells restored KIT phosphorylation during imatinib treatment, allowing sensitive cells to proliferate in the presence of the drug. FGF2 expression was increased in imatinib-resistant GIST cells, the growth of which was blocked by RNAi-mediated silencing of FGFR3. Moreover, combining KIT and FGFR3 inhibitors synergized to block the growth of imatinib-resistant cells. Signaling crosstalk between KIT and FGFR3 activated the MAPK pathway to promote resistance to imatinib. Clinically, an IHC analysis of tumor specimens from imatinib-resistant GIST patients revealed a relative increase in FGF2 levels, with a trend toward increased expression in imatinib-naïve samples consistent with possible involvement in drug resistance. Our findings provide a mechanistic rationale to evaluate existing FGFR inhibitors and multikinase inhibitors that target FGFR3 as promising strategies to improve treatment of patients with GIST with de novo or acquired resistance to imatinib.
authors.affiliation: Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon. Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, Oregon.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Javidi-Sharifi
authors.affiliation: Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon. Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, Oregon.
authors.forename: Elie
authors.initials: E
authors.lastname: Traer
authors.affiliation: Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Martinez
authors.affiliation: Department of Molecular Genetics, Lerner Research Institute, Cleveland, Ohio.
authors.forename: Anu
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Division of Human Health and Medical Science, Graduate School of Kuroshio Science, Kochi University, Nankoku, Kochi, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Taguchi
authors.affiliation: Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon. Department of Anatomic Pathology, Oregon Health and Science University, Portland, Oregon.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Dunlap
authors.affiliation: Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon. Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, Oregon. Portland VA Medical Center, Portland, Oregon.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Heinrich
authors.affiliation: Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon. Department of Anatomic Pathology, Oregon Health and Science University, Portland, Oregon.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Corless
authors.affiliation: Department of Molecular Genetics, Lerner Research Institute, Cleveland, Ohio. Taussig Cancer Center, Cleveland Clinic, Cleveland, Ohio. Department of Anatomic Pathology, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Rubin
authors.affiliation: Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon. Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, Oregon. Howard Hughes Medical Institute, Portland, Oregon.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.affiliation: Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon. Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, Oregon. tynerj@ohsu.edu.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Tyner
mesh_terms: D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D000068877:Imatinib Mesylate; D047468:Immunoprecipitation; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009154:Mutation; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D020239:Receptor Cross-Talk; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D001549:Benzamides; C115711:PD 173074; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D034741:RNA, Small Interfering; D000068877:Imatinib Mesylate; C496365:FGFR3 protein, human; D019009:Proto-Oncogene Proteins c-kit; D051498:Receptor, Fibroblast Growth Factor, Type 3