Targeting FGFR3 in multiple myeloma: inhibition of t(4;14)-positive cells by SU5402 and PD173074

Abstract

The t(4;14)(p16.3;q32), associated with 10-20% of cases of multiple myeloma (MM), deregulates the expression of MMSET and FGFR3. To assess the potential of FGFR3 as a drug target, we evaluated the effects of selective inhibitors on MM and control cell lines. SU5402 and PD173074 specifically inhibited the growth of the two t(4;14)-positive MM lines, KMS-11 and OPM-2. Importantly, inhibition was still observed in the presence of IL-6, a growth factor known to play an important role in MM. Both compounds induced a dose-dependent reduction in cell viability and an increase in apoptosis, accompanied by a decrease in extracellular signal-related kinase phosphorylation. In contrast, no inhibition was seen with either compound against t(4;14)-negative cell lines or NCI-H929, a t(4;14)-positive, FGFR3-negative MM cell line. FGFR3 is thus a plausible candidate for targeted therapy in a subset of MM patients.

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

“…With the growing interest in targeting FGFR, broad studies such as those presented here will help define the pharmacologic profile of a specific FGFR inhibitor across a relevant panel of preclinical systems. Several studies in defined tumor types have been conducted with PD173074 (12,31,32), but they predominantly use engineered cell lines or those representing a single disease type. A lack of small molecule and biological inhibitors specific for FGFR and a lack of well-characterized reagents have, to date, prevented similar studies.…”

“…Several molecules are or have been investigated with the aim of potentially exploiting their FGFR activity. PD173074 showed selectivity for the FGFR receptor in vitro and a number of reports described its activity in individual FGFRdependent systems (12,14), but it did not proceed into clinical development. Compounds explored clinically include brivanib alaninate (BMS-582664; ref 29,33) in hepatocellular carcinoma (NCT00355238), endometrial (NCT00888173), and colorectal cancer (NCT00207051) and TKI-258 (Novartis) in multiple myeloma (NCT01058434), renal cell carcinoma (NCT00715182), urothelial cell carcinoma (NCT00790426), and breast cancer (NCT 00958971).…”

“…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.…”

A Novel, Selective Inhibitor of Fibroblast Growth Factor Receptors That Shows a Potent Broad Spectrum of Antitumor Activity in Several Tumor Xenograft Models

“…To further establish that LY2874455 specifically inhibits FGFR in the cell, we tested this molecule in a cell proliferation assay to assess its ability to inhibit different multiple myeloma cancer cell lines, some of which (KMS-11 and OPM-2 cells) carry an FGFR3 chromosomal translocation, resulting in the overexpression of FGFR3 (40,41). In this study, we also used L-363 and U266, known to contain little or no FGFR3 (41).…”

Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma

“…Inhibition of wild-type and constitutively activated FGFR-3 autophosphorylation in human MM cell lines by the FGFR-specific tyrosine kinase inhibitors SU5402, SU10991, PD173074 or CHIR258 is associated with decreased viability and tumor cell growth arrest, both in vitro and in vivo in a murine model (Grand et al, 2004;Trudel et al, 2004Trudel et al, , 2005.…”