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.

Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice

“…While small molecule compounds that can inhibit FGFR3 kinase activity have been described (18)(19)(20)(21)(22)44), the close homology of the kinase domains within the FGFR family has hampered the development of FGFR3-selective inhibitors. The lack of selectivity of the reported inhibitors makes it difficult to discern the relative contribution of FGFR3 to the biology of specific cancer types; further, it may carry safety liabilities, capping maximal dose levels and thus limiting optimal inhibition of FGFR3.…”

“…Accordingly, FGFR3 has been proposed as a potential therapeutic target in multiple myeloma. Indeed, several small-molecule inhibitors targeting FGFRs, although not selective for FGFR3 and having cross-inhibitory activity toward certain other kinases, have demonstrated cytotoxicity against FGFR3-positive myeloma cells in culture and in mouse models (18)(19)(20)(21)(22).…”

Mosaicism of activatingFGFR3 mutations in human skin causes epidermal nevi

“…PKC412 is currently being evaluated in phase II trials for acute myeloid leukemia patients (55). This molecule effectively inhibits the tyrosine kinase activity of FGFR3, as shown by the (55). A broader use of this drug in other disorders associated with an increased activity of FGFR3 has been suggested.…”

“…They have been used in vitro and in animal models to inhibit the growth of multiple myeloma cell lines with activating FGFR3 mutations (51)(52)(53)(54). PKC412 is currently being evaluated in phase II trials for acute myeloid leukemia patients (55). This molecule effectively inhibits the tyrosine kinase activity of FGFR3, as shown by the (55).…”

Potent, Selective Inhibitors of Fibroblast Growth Factor Receptor Define Fibroblast Growth Factor Dependence in Preclinical Cancer Models

“…The overexpressed FGFR3 is usually wild type and although somatic mutations are occasionally found, the cells remain sensitive to FGF (7). Activated FGFR3 has a role in myelomagenesis and the ability of anti-FGFR3 antibodies and kinase inhibitors, for example, PD173074 and CHIR258, to inhibit multiple myeloma cell growth, both in vitro and in vivo, validates FGFR3 as a therapeutic target (8)(9)(10)(11)(12)(13)(14)(15)(16)(17). The FGFR2 gene is amplified in some cases of gastric cancer, resulting in a highly overexpressed and constitutively active receptor.…”