Inhibition of fibroblast growth factor receptor 3 induces differentiation and apoptosis in t(4;14) myeloma

Abstract

We have previously shown that dysregulation of fibroblast growth factor receptor 3 (FGFR3) by the t(4;14) translocation is a primary event in multiple myeloma (MM) and that activating mutations of FGFR3 are acquired in some cases. We describe here inhibition of wild-type (WT) and constitutively activated mutant IntroductionThe inhibition of the primary genetic lesion (BCR-ABL, PML-RAR␣) can induce differentiation and apoptosis in human myeloid tumors. 1,2 Transient inactivation of MYC in an MYC transgenic mouse tumor model results in tumor cell differentiation, followed by apoptosis on subsequent MYC reactivation. 3 We wondered to what extent these observations can be generalized to other human cancers and, in particular, to lymphoid malignancies. There are 3 main reasons why this has been difficult: (1) the challenge in identifying genes that participate in the primary oncogenic process, (2) the lack of specific molecular inhibitors, and (3) the need for a well-ordered model of cell differentiation.B-cell differentiation to plasma cells (PCs) provides one such model. Following isotype switch recombination centrocytic B cells differentiate into low-rate immunoglobulin (Ig)-secreting plasmablastic cells, migrate to the bone marrow (BM), and proliferate as immature plasmablasts. 4,5 Differentiation of BM plasmablastic cells into high-rate Ig-secreting PCs is the final step to long-lived PCs, the end-stage of B-cell differentiation. Multiple myeloma (MM) has typically been defined as a neoplasm of terminally differentiated PCs; however, in contrast to fully differentiated PCs that do not proliferate, myeloma cells proliferate slowly and secrete significantly lower amounts of Ig. 6,7 The t(4;14) translocation, which occurs in approximately 15% of patients with MM, appears to be mediated by errors in isotype switch recombination and results in the dysregulated expression of 2 genes, FGFR3 and MMSET. 8,9 In particular, wild-type (WT) FGFR3, which is not normally expressed by B cells or PCs, becomes ectopically expressed at very high levels (M.C., unpublished data, November 1998).WT FGFR3 induces proliferative signals in myeloma cells and appears to be weakly transforming in a hematopoietic mouse model. 10,11 The subsequent acquisition of FGFR3-activating mutations in some MM is clearly associated with disease progression and is strongly transforming in several experimental models. 11,12 The clinical impact of t(4; 14) translocations has been demonstrated in 3 large studies each reporting a marked reduction in overall survival [13][14][15] with no apparent therapeutic benefit from high-dose chemotherapy. The clinical significance of FGFR3 expression, however, remains somewhat ambiguous, because Keats and colleagues found that t(4;14) conferred a poor prognosis irrespective of FGFR3 expression. Indeed, FGFR3 is not up-regulated in all cases of t(4;14) myeloma, and it has been found that the der14 chromosome can be lost in primary samples and cell lines. 14,16,17 These results suggest that if ectopic expression of WT FG...

Heterogeneity of t(4;14) in multiple myeloma. Long-term follow-up of 100 cases treated with tandem transplantation in IFM99 trials

“…New targeted therapies such as FGFR3 inhibitor currently evaluated in prospective protocols could also improve the outcome of this aggressive disease in patients expressing FGFR3. 21,28 46 vs 300 pts Heterogeneity of t(4;14) in multiple myeloma P Moreau et al…”

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.…”

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.…”