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Fibroblast Growth Factor Receptor Inhibitors As a Cancer Treatment: from a Biologic Rationale to Medical Perspectives

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Fibroblast Growth Factor Receptor Inhibitors As a Cancer Treatment: from a Biologic Rationale to Medical Perspectives Published OnlineFirst February 15, 2013; DOI: 10.1158/2159-8290.CD-12-0362 REVIEW Fibroblast Growth Factor Receptor Inhibitors as a Cancer Treatment: From a Biologic Rationale to Medical Perspectives Maria Vittoria Dieci 1 , 3 , 5 , Monica Arnedos 1 , 3 , Fabrice Andre 1 , 3 , 4 , and Jean Charles Soria2 , 3 , 4 ABSTRACT The fi broblast growth factor/fi broblast growth factor receptor (FGF/FGFR) sig- naling pathway plays a fundamental role in many physiologic processes, includ- ing embryogenesis, adult tissue homeostasis, and wound healing, by orchestrating angiogenesis. Ligand-independent and ligand-dependent activation have been implicated in a broad range of human malignancies and promote cancer progression in tumors driven by FGF/FGFR oncogenic mutations or amplifi cations, tumor neoangiogenesis, and targeted treatment resistance, thereby supporting a strong rationale for anti-FGF/FGFR agent development. Efforts are being pursued to develop selective approaches for use against this pathway by optimizing the management of emerging, class- specifi c toxicity profi les and correctly designing clinical trials to address these different issues. Signifi cance: FGF/FGFR pathway deregulations are increasingly recognized across different human cancers. Understanding the mechanisms at the basis of these alterations and their multiple roles in cancer promotion and drug resistance is a fundamental step for further implementation of targeted therapies and research strategies. Cancer Discov; 3(3); 1–16. ©2012 AACR. INTRODUCTION like FGFs (i.e., FGF19, 21, and 23) and canonical FGFs (i.e., FGF1–10, 16–18, and 20). The FGF–FGFR interaction is sta- Fibroblast growth factors (FGF) that create signals by bind- bilized by the formation of a ternary complex that involves ing with FGF receptors (FGFR) play a critical role in many either cell surface heparan sulfate proteoglycans (HPSG) or physiologic processes. Compelling evidence indicates that Klotho proteins that further increase the specifi city of the aberrant FGF signaling is also involved in the pathogenesis interaction in the case of hormonal FGFs ( 1 ). of many malignancies. A growing body of research indicates Four of 5 identifi ed FGFRs (i.e., FGFR1–4) are single-pass, that the inhibition of the FGF pathway may present an effec- transmembrane, tyrosine kinase receptors ( Fig. 1 ). The extracel- tive therapeutic option for cancer. lular domain contains 3 immunoglobulin (Ig)–like fragments This review will summarize the involvement of the FGF (Ig-I, -II, and -III). Ig-I and the acid box are supposed to have pathway in cancer progression, examine the current clinical a role in receptor autoinhibition, whereas Ig-II and Ig-III bind data for FGFR inhibitors, and discuss the challenges associ- ligands and HPSGs ( 1 ). Alternative splicing of the second half ated with developing FGFR inhibitors. of the Ig-III extracellular fragment of FGFR1, 2, or 3 may gener- ate isoforms, that is, Ig-IIIb and Ig-IIIc, which are specifi cally FGFs AND FGFRs IN HUMAN PHYSIOLOGY expressed in the epithelium and mesenchyme, respectively, and FGFs and FGFRs differ in terms of ligand-binding specifi city ( 2 ). The cytoplasmic The FGF ligand family contains 18 known components portion of FGFR1–4 contains a tyrosine kinase domain and a that can be divided into the following 2 categories: hormone- COOH tail. A fi fth receptor, FGFRL1, also binds FGFs, but it lacks the tyrosine kinase domain; moreover, FGFRL1 reportedly Authors’ Affi liations: 1 Breast Cancer Unit and 2 Early Drug Development reduces cell growth and accelerates cell differentiation ( 3 ). Unit (SITEP), Department of Medical Oncology; 3 INSERM Unit U981, Gus- The specifi city of the FGF–FGFR interaction is established tave Roussy Institute, Villejuif; 4 Paris Sud University, Orsay, France; and through the different ligand-binding capacities of FGFRs as well 5 Department of Oncology, Hematology, and Respiratory Diseases, Univer- as the alternative splicing of FGFR mRNA, and the tissue-specifi c sity Hospital, Modena, Italy expression of ligands, receptors, and cell-surface proteins. Corresponding Author: Fabrice Andre, Comité 050, Gustave Roussy Insti- tute, 114 rue E Vaillant, 94800 Villejuif, France. Phone: 003-314-211- 4371; Fax: 003-314-211-5274; E-mail: [email protected] FGF/FGFR Signaling doi: 10.1158/2159-8290.CD-12-0362 The binding of an FGF to an FGFR induces receptor © 2012 American Association for Cancer Research. dimerization, thereby enabling the intermolecular OF1 | CANCER DISCOVERYMARCH 2013 www.aacrjournals.org Downloaded from cancerdiscovery.aacrjournals.org on September 25, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst February 15, 2013; DOI: 10.1158/2159-8290.CD-12-0362 Targeting FGFR Signaling in Human Cancer REVIEW Ig-I Acid box Ig-II HPSG FGF Ig-III Plasma membrane SEF FGFRL1 RAS SPRY FRS2 FRS2 P P SOS GRB2 GRB2 P P RAF P P PIP2 PLC-γ P P PKC DAG PI3K PIP3 MEK STAT MKP1 MAPK AKT MKP3 = Negative regulator Nucleus = Tyrosine kinase domain Figure 1. The FGFR structure and signaling network. FGFRs are single-pass transmembrane receptors with an extracellular domain comprising 3 Ig-like domains (Ig-I–III) and an intracellular tyrosine kinase domain. The ligand-receptor binding is stabilized by the interaction with HPSG, thus inducing recep- tor dimerization and transphosphorylation at several tyrosine residues in the intracellular portion of FGFR. Two main downstream pathways are shown. The fi rst induces Ras-dependent MAPK signaling, and the second leads to PI3K/Akt activation, independently and in parallel with Ras. PLC-γ may also be activated, thus triggering PKC, which converges with the MAPK pathway. Other pathways may be switched on, such as the STAT-dependent pathway. Many negative regulators are able to attenuate signaling at different levels, including FGFRL1, SEF, SPRY, and MAPK phosphatase 1 and 3 (MKP1 and MKP3) MEK, MAP-ERK kinase. transphosphorylation of several tyrosine residues in the Negative feedback loops involve the induction of MAPK COOH terminal tail, kinase domains, and juxtamembrane phosphatase 3 (MAPK3), Sprouty (Spry) proteins, and “similar region. The activated FGFR phosphorylates FGFR substrate 2 expression to FGF” (SEF) family members, which can attenu- (FRS2) and recruits growth factor receptor-bound 2 (GRB2), ate the signal cascade at different levels. Moreover, following fi nally resulting in the activation of RAS and the downstream activation, the receptor is internalized and then degraded or RAS/mitogen-activated protein kinase (MAPK) pathway. recycled, partly depending on the extent of ubiquitination ( 4 ). Likewise, GRB2 activates phosphoinositide 3-kinase (PI3K)/ AKT-dependent signaling. Operating independently from Biologic and Context-Dependent Responses FRS2, phospholipase C-γ (PLC-γ) binds to a phosphotyro- FGFRs/FGFs are key molecules involved in embryogenesis, sine at the COOH tail and hydrolyzes phosphatidylinositol tissue homeostasis, tissue repair, wound healing, and infl am- 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-tri- mation ( 5 ). The main effects of the FGFR pathway include phosphate (PIP3) and diacylglycerol (DAG), thus activating proliferation, migration, and antiapoptotic signals. Prolifera- protein kinase C (PKC), which converges with the MAPK tion is mainly achieved through the MAPK cascade, whereas pathway ( Fig. 1 ; ref. 4 ). antiapoptotic signals are mediated by PI3K/AKT with MARCH 2013CANCER DISCOVERY | OF2 Downloaded from cancerdiscovery.aacrjournals.org on September 25, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst February 15, 2013; DOI: 10.1158/2159-8290.CD-12-0362 REVIEW Dieci et al. therapeutic targets for specifi c cancers, and the details of STATEMENTS OF RELEVANCE these targets are discussed subsequently. • FGF/FGFR oncogenic driver mutations/amplifi cations FGFR1 characterize rare tumor segments across various The most convincing evidence for the involvement of cancer types, and FGFR pathway activation may act FGFR signaling in cancer progression is provided by the as a resistance mechanism to targeted and antiang- hematologic fi eld. For example, the 8p11 myeloproliferative iogenic drugs. syndrome is an aggressive neoplasm characterized by rapid • Data from phase I/II trials suggest that FGFR inhibi- acute leukemic transformation. To date, almost 70 cases have tors exhibit antitumor activity and should be further been reported, and either a translocation or an insertion at advanced in the clinical development process. the 8p11 locus harboring the FGFR1 gene has been linked • Targeting the FGF/FGFR pathway in human cancer rep- to the disease. The permanently activated fusion proteins resents an illustration of the current challenges in drug consist of an N-terminal portion with a dimerization domain development: how to develop drugs in rare genomic and the C-terminal portion that houses the FGFR1 tyrosine segments; how to develop compounds that aim at kinase domain ( 18 ). The most common translocation is reversing resistance to conventional agents; and how t(8;13)(p11;q12) and involves ZNF198. Preclinical evidence to better target the host, including angiogenesis. shows that FGFR inhibitors are able to reduce growth and induce apoptosis in cell lines harboring FGFR1 gene rear- rangements ( 37 ). cross-talk between both pathways ( 4 ). However, in specifi c cel- The FGFR1 gene also frequently exhibits alterations in lular contexts, FGF signaling may induce growth arrest and other diseases. Indeed, the amplifi
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