title: FGFR3 as a therapeutic target of the small molecule inhibitor PKC412 in hematopoietic malignancies.
abstract: Reccurent chromosomal translocation t(4;14) (p16.3;q32.3) occurs in patients with multiple myeloma (MM) and is associated with ectopic overexpression of fibroblast growth factor receptor 3 (FGFR3) that sometimes may contain the activation mutations such as K650E thanatophoric dysplasia type II (TDII). Although there have been significant advances in therapy for MM including the use of proteasome inhibitors, t(4;14) MM has a particularly poor prognosis and most patients still die from complications related to their disease or therapy. One potential therapeutic strategy is to inhibit FGFR3 in those myeloma patients that overexpress the receptor tyrosine kinase due to chromosomal translocation. Here we evaluated PKC412, a small molecule tyrosine kinase inhibitor, for treatment of FGFR3-induced hematopoietic malignancies. PKC412 inhibited kinase activation and proliferation of hematopoietic Ba/F3 cells transformed by FGFR3 TDII or a TEL-FGFR3 fusion. Similar results were obtained in PKC412 inhibition of several different t(4;14)-positive human MM cell lines. Furthermore, treatment with PKC412 resulted in a statistically significant prolongation of survival in murine bone marrow transplant models of FGFR3 TDII-induced pre-B cell lymphoma, or a peripheral T-cell lymphoma associated TEL-FGFR3 fusion-induced myeloproliferative disease. These data indicate that PKC412 may be a useful molecularly targeted therapy for MM associated with overexpression of FGFR3, and perhaps other diseases associated with dysregulation of FGFR3 or related mutants.
authors.affiliation: Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Lee
authors.forename: Ifor R
authors.initials: IR
authors.lastname: Williams
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Kutok
authors.forename: Constantine S
authors.initials: CS
authors.lastname: Mitsiades
authors.forename: Nicole
authors.initials: N
authors.lastname: Duclos
authors.forename: Sarah
authors.initials: S
authors.lastname: Cohen
authors.forename: Jennifer
authors.initials: J
authors.lastname: Adelsperger
authors.forename: Rachel
authors.initials: R
authors.lastname: Okabe
authors.forename: Allison
authors.initials: A
authors.lastname: Coburn
authors.forename: Sandra
authors.initials: S
authors.lastname: Moore
authors.forename: Brian J P
authors.initials: BJ
authors.lastname: Huntly
authors.forename: Doriano
authors.initials: D
authors.lastname: Fabbro
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.forename: James D
authors.initials: JD
authors.lastname: Griffin
authors.forename: Dwight Gary
authors.initials: DG
authors.lastname: Gilliland
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006131:Growth Inhibitors / Q000494:pharmacology; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism; D009196:Myeloproliferative Disorders / Q000188:drug therapy / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013796:Thanatophoric Dysplasia / Q000188:drug therapy / Q000378:metabolism; D014162:Transfection
chemical_list: D006131:Growth Inhibitors; D011993:Recombinant Fusion Proteins; C496366:Fgfr3 protein, mouse; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3; D019311:Staurosporine; C059539:midostaurin