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Targeting FGFR Signaling in Cancer Mehdi Touat1,2, Ecaterina Ileana1, Sophie Postel-Vinay1,2, Fabrice Andre2,3, and Jean-Charles Soria1,2

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Targeting FGFR Signaling in Cancer Mehdi Touat1,2, Ecaterina Ileana1, Sophie Postel-Vinay1,2, Fabrice Andre�2,3, and Jean-Charles Soria1,2 Review Clinical Cancer Research Targeting FGFR Signaling in Cancer Mehdi Touat1,2, Ecaterina Ileana1, Sophie Postel-Vinay1,2, Fabrice Andre2,3, and Jean-Charles Soria1,2 Abstract The fibroblast growth factor signaling pathway (FGFR signal- profiles in early-phase trials. Promising treatment efficacy has ing) is an evolutionary conserved signaling cascade that regulates been observed in different types of malignancies, particularly in several basic biologic processes, including tissue development, tumors harboring aberrant FGFR signaling, thus offering novel angiogenesis, and tissue regeneration. Substantial evidence indi- therapeutic opportunities in the era of precision medicine. The cates that aberrant FGFR signaling is involved in the pathogenesis most exciting challenges now focus on selecting patients who are of cancer. Recent developments of deep sequencing technologies most likely to benefit from these agents, increasing the efficacy of have allowed the discovery of frequent molecular alterations in therapies with the development of novel potent compounds and components of FGFR signaling among several solid tumor types. combination strategies, and overcoming toxicities associated with Moreover, compelling preclinical models have demonstrated the FGFR inhibitors. After examination of the basic and translational oncogenic potential of these aberrations in driving tumor growth, research studies that validated the oncogenic potential of aberrant promoting angiogenesis, and conferring resistance mechanisms FGFR signaling, this review focuses on recent data from clinical to anticancer therapies. Recently, the field of FGFR targeting has trials evaluating FGFR targeting therapies and discusses the chal- exponentially progressed thanks to the development of novel lenges and perspectives for the development of these agents. Clin agents inhibiting FGFs or FGFRs, which had manageable safety Cancer Res; 21(12); 2684–94. Ó2015 AACR. Disclosure of Potential Conflicts of Interest F. Andre is a consultant/advisory board member for Novartis. J.-C. Soria is a consultant/advisory board member for AstraZeneca, Clovis Oncology, EOS, Johnson & Johnson, and Servier. No potential conflicts of interest were disclosed by the other authors. Editor's Disclosures The following editor(s) reported relevant financial relationships: S.E. Bates reports receiving a commercial research grant from Celgene via CRADA with NCI. CME Staff Planners' Disclosures The members of the planning committee have no real or apparent conflicts of interest to disclose. Learning Objectives Upon completion of this activity, the participant should have a better understanding of the biologic rationale for targeting the FGFR signaling pathway in cancer, and of the different approaches currently under clinical development. Acknowledgment of Financial or Other Support This activity does not receive commercial support. Introduction embryonic development, differentiation, proliferation, survival, migration, and angiogenesis. FGFR signaling components are Fibroblast growth factors (FGF) and their receptors (FGFR) frequently altered in human cancer, and several preclinical mod- regulate a wide range of physiologic cellular processes, such as els have provided compelling evidence for the oncogenic poten- tial of aberrant FGFR signaling in carcinogenesis, thereby validat- ing FGFR signaling as an attractive target for cancer treatment. 1 Drug Development Department (DITEP), Gustave Roussy, Villejuif, Depending on the type of genomic aberration and the cellular France. 2University Paris Sud, INSERM U981, Predictive Biomarkers and New Therapeutic Strategies in Oncology,Gustave Roussy,Villejuif, context, the oncogenic potential of dysregulated FGFR signaling France. 3Department of Medical Oncology, Gustave Roussy, Villejuif, ranges from a driver event—responsible for oncogenesis and France. oncogene addiction—to an escape mechanism of secondary Corresponding Author: Fabrice Andre, Gustave Roussy Institute, 114 rue E acquired resistance to other anticancer agents. Vaillant, Villejuif 94800, France. Phone: þ33-1-42-11-43-71; Fax: þ33-1-42-11- 52-74; E-mail: [email protected] FGFR Signaling Pathway doi: 10.1158/1078-0432.CCR-14-2329 FGFRs are transmembrane, receptor tyrosine kinases (RTK) Ó2015 American Association for Cancer Research. consisting of three extracellular immunoglobulin-like domains 2684 Clin Cancer Res; 21(12) June 15, 2015 Downloaded from clincancerres.aacrjournals.org on July 20, 2015. © 2015 American Association for Cancer Research. Targeting FGFR Signaling in Cancer FGF FGF Extracellular FGF FGF FGFR HSPG FGF FGF Plasma membrane SEF FGFRL1 P P SPRY RAS RAF P P PIP2 P P FRS2 P P GRB2 SOS Cytoplasm PLC-γ GAB1 MEK IP3 P P DAG P P STAT PI3K ERK MKP3 PKC AKT Nucleus MKP1 Transcription of target genes Proliferation Resistance to Neoangiogenesis and survival anticancer agents © 2015 American Association for Cancer Research Figure 1. FGFR structure, network, and dysregulation in cancer. FGFRs are transmembrane RTKs consisting of three extracellular immunoglobulin-like domains and one intracellular split tyrosine kinase domain. A complex is formed among FGF, HSPG, and FGFR leading to receptor dimerization, and transphosphorylation of tyrosine kinase domains. Activation of downstream signaling occurs via FRS2, which functions as a key adaptor protein associated with GRB2, resulting in subsequent activation of MAPK and PI3K/AKT signaling pathways. Operating independently from FRS2, phospholipase C-g (PLC-g) binds to a phosphotyrosine at the COOH tail and hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-tri-phosphate (IP3) and diacylglycerol (DAG), thus activating protein kinase C (PKC), which converges with the MAPK pathway. Depending on the cellular context, several other pathways may be activated by FGFRs, including the p38 MAPK and Jun N-terminal kinase pathways, STAT signaling, and ribosomal protein S6 kinase 2 (RSK2). Multiple negative regulators may attenuate signaling at different levels, including FGFRL1, SEF, SPRY, and MAPK phosphatase 1 and 3 (MKP1 and MKP3). Aberrant FGFR signaling may result from (i) increased availability of FGFs (secreted by tumor or stromal cells) leading to ligand-dependent FGFR signaling (autocrine/paracrine loops), or (ii) ligand-independent FGFR signaling when a molecular alteration of an FGFR (mutation, translocation, or amplification) induces a constitutive activation of the kinase domain. and one intracellular split tyrosine kinase domain (1, 2). In FGFs are secreted glycoproteins that are readily sequestered by contrast with the multiple fibroblast growth factor (FGF) genes the extracellular matrix and the cell surface by heparan sulfate encoding 22 functionally distinct ligands, only four different proteoglycans (HPSG), which stabilize the FGF–FGFR interac- FGFRs (FGFR1–4) are known. However, alternative splicing tion by protecting FGFs from protease-mediated degradation. events of FGFR1–3 allow the generation of multiple isoforms, The binding of an FGF to an FGFR leads to receptor dimerization presenting a dramatically variable FGF-binding specificity (3). and transphosphorylation of tyrosine kinase domains (Fig. 1; www.aacrjournals.org Clin Cancer Res; 21(12) June 15, 2015 2685 Downloaded from clincancerres.aacrjournals.org on July 20, 2015. © 2015 American Association for Cancer Research. Touat et al. refs. 4, 5). Activation of downstream signaling occurs via the potential of these alterations, and high sensitivity to FGFR intracellular receptor substrates FGFR substrate 2 (FRS2) and inhibitors (17). phospholipase Cg (PLC-g), leading to subsequent upregulation These preclinical data provide a strong rationale for enrolling of RAS/mitogen-activated protein kinase (MAPK) and phosphoi- patients with tumors harboring FGFR fusions in clinical trials nositide 3-kinase (PI3K)/AKT signaling pathways. Other path- evaluating FGFR inhibitors, and preliminary data from early- ways can be activated, including STAT-dependent signaling phase trials are very encouraging (18). (Fig. 1; refs. 1–5). FGFR-activating mutations. The screening of more than 1,000 Dysregulation of FGFR Signaling in Human exon mutations of protein kinase genes from 210 different malig- fi Malignancies nancies (19) identi ed the FGFR signaling pathway as the most commonly mutated tyrosine kinase signaling pathway. Activating Aberrant FGFR signaling contributes to carcinogenesis in three mutations in FGFRs may result in aberrant FGFR signaling main situations: (i) "driver mutations," where the acquisition of through multiple mechanisms, including the following: (i) somatic molecular alterations directly stimulates cancer cell pro- enhanced activation of the kinase domain; (ii) ligand-indepen- liferation and survival; (ii) neoangiogenesis; and (iii) resistance to dent dimerization of the receptors; and (iii) altered affinity for anticancer agents (1–5). FGF ligands. Urothelial bladder carcinoma has the most established associ- Molecular alterations of the FGFR signaling pathway as driver ation with altered FGFR signaling, with up to 80% of low-grade events: the oncogene addiction phenomenon tumors harboring FGFR mutations and compelling in vivo and in FGFR family fusion genes. Fusion genes are hybrid genes formed by vitro data (Table 1). Comprehensive molecular characterization of the rearrangement of two previously independent genes. They can this cancer (16) revealed a cluster of tumors with papillary mor- occur as a result of translocation, chromosomal inversion,
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