Skip to main content
  • AACR Publications
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

AACR logo

  • Register
  • Log in
  • My Cart
Advertisement

Main menu

  • Home
  • About
    • The Journal
    • AACR Journals
    • Journal Sections
    • Subscriptions
    • Permissions and Reprints
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Collections
      • COVID-19 & Cancer Resource Center
      • Precision Medicine and Therapeutic Resistance
      • Clinical Trials
      • Immuno-oncology
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
    • Journal Press Releases
  • COVID-19
  • Webinars
  • 10th Anniversary
  • Search More

    Advanced Search

  • AACR Publications
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

User menu

  • Register
  • Log in
  • My Cart

Search

  • Advanced search
Cancer Discovery
Cancer Discovery
  • Home
  • About
    • The Journal
    • AACR Journals
    • Journal Sections
    • Subscriptions
    • Permissions and Reprints
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Collections
      • COVID-19 & Cancer Resource Center
      • Precision Medicine and Therapeutic Resistance
      • Clinical Trials
      • Immuno-oncology
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
    • Journal Press Releases
  • COVID-19
  • Webinars
  • 10th Anniversary
  • Search More

    Advanced Search

Review

Fibroblast Growth Factor Receptor Inhibitors as a Cancer Treatment: From a Biologic Rationale to Medical Perspectives

Maria Vittoria Dieci, Monica Arnedos, Fabrice Andre and Jean Charles Soria
Maria Vittoria Dieci
1Breast Cancer Unit and 2Early Drug Development Unit (SITEP), Department of Medical Oncology; 3INSERM Unit U981, Gustave Roussy Institute, Villejuif; 4Paris Sud University, Orsay, France; and 5Department of Oncology, Hematology, and Respiratory Diseases, University Hospital, Modena, Italy
1Breast Cancer Unit and 2Early Drug Development Unit (SITEP), Department of Medical Oncology; 3INSERM Unit U981, Gustave Roussy Institute, Villejuif; 4Paris Sud University, Orsay, France; and 5Department of Oncology, Hematology, and Respiratory Diseases, University Hospital, Modena, Italy
1Breast Cancer Unit and 2Early Drug Development Unit (SITEP), Department of Medical Oncology; 3INSERM Unit U981, Gustave Roussy Institute, Villejuif; 4Paris Sud University, Orsay, France; and 5Department of Oncology, Hematology, and Respiratory Diseases, University Hospital, Modena, Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Monica Arnedos
1Breast Cancer Unit and 2Early Drug Development Unit (SITEP), Department of Medical Oncology; 3INSERM Unit U981, Gustave Roussy Institute, Villejuif; 4Paris Sud University, Orsay, France; and 5Department of Oncology, Hematology, and Respiratory Diseases, University Hospital, Modena, Italy
1Breast Cancer Unit and 2Early Drug Development Unit (SITEP), Department of Medical Oncology; 3INSERM Unit U981, Gustave Roussy Institute, Villejuif; 4Paris Sud University, Orsay, France; and 5Department of Oncology, Hematology, and Respiratory Diseases, University Hospital, Modena, Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Fabrice Andre
1Breast Cancer Unit and 2Early Drug Development Unit (SITEP), Department of Medical Oncology; 3INSERM Unit U981, Gustave Roussy Institute, Villejuif; 4Paris Sud University, Orsay, France; and 5Department of Oncology, Hematology, and Respiratory Diseases, University Hospital, Modena, Italy
1Breast Cancer Unit and 2Early Drug Development Unit (SITEP), Department of Medical Oncology; 3INSERM Unit U981, Gustave Roussy Institute, Villejuif; 4Paris Sud University, Orsay, France; and 5Department of Oncology, Hematology, and Respiratory Diseases, University Hospital, Modena, Italy
1Breast Cancer Unit and 2Early Drug Development Unit (SITEP), Department of Medical Oncology; 3INSERM Unit U981, Gustave Roussy Institute, Villejuif; 4Paris Sud University, Orsay, France; and 5Department of Oncology, Hematology, and Respiratory Diseases, University Hospital, Modena, Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jean Charles Soria
1Breast Cancer Unit and 2Early Drug Development Unit (SITEP), Department of Medical Oncology; 3INSERM Unit U981, Gustave Roussy Institute, Villejuif; 4Paris Sud University, Orsay, France; and 5Department of Oncology, Hematology, and Respiratory Diseases, University Hospital, Modena, Italy
1Breast Cancer Unit and 2Early Drug Development Unit (SITEP), Department of Medical Oncology; 3INSERM Unit U981, Gustave Roussy Institute, Villejuif; 4Paris Sud University, Orsay, France; and 5Department of Oncology, Hematology, and Respiratory Diseases, University Hospital, Modena, Italy
1Breast Cancer Unit and 2Early Drug Development Unit (SITEP), Department of Medical Oncology; 3INSERM Unit U981, Gustave Roussy Institute, Villejuif; 4Paris Sud University, Orsay, France; and 5Department of Oncology, Hematology, and Respiratory Diseases, University Hospital, Modena, Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
DOI: 10.1158/2159-8290.CD-12-0362 Published March 2013
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Article Figures & Data

Figures

  • Tables
  • Figure 1.
    • Download figure
    • Open in new tab
    • Download powerpoint
    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 receptor dimerization and transphosphorylation at several tyrosine residues in the intracellular portion of FGFR. Two main downstream pathways are shown. The first 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.

  • Figure 2.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure 2.

    Challenges and open questions in anti-FGFR drug development.

Tables

  • Figures
  • Table 1.

    Activating genetic alterations in FGFR and related cancer types

    GeneAlterationCancer type (incidence, if known; reference)
    FGFR1AmplificationSquamous NSCLC (20%; ref. 9)
    Breast cancer (10%; ref. 10)
    Ovarian cancer (∼5%; ref. 11)
    Bladder cancer (3%; ref. 12)
    Others: oral squamous cell carcinoma, esophageal squamous carcinoma, prostate cancer (13–15)
    MutationMelanoma (rare), glioblastoma (16, 17)
    Translocation8p11 myeloproliferative syndrome, chronic myeloid leukemia (rare; refs. 18, 19)
    FGFR2AmplificationGastric cancer (10%; ref. 20)
    Breast cancer (4% of triple-negative cases; ref. 21)
    MutationEndometrial cancer (12%; ref. 22)
    Squamous NSLC (5%; ref. 8)
    Gastric cancer (rare; ref. 23)
    Germline SNPSecond intron SNP: breast cancer susceptibility (24)
    FGFR3AmplificationBladder cancer (25)
    Salivary adenoid cystic cancer (26)
    MutationBladder cancer (50–60% non-muscle invasive; 10–15% muscle invasive; ref. 27)
    Cervical cancer (5%; ref. 28)
    Myeloma (5% of the translocated cases; ref. 29)
    Prostate cancer (3%; ref. 30)
    Spermatocytic seminoma (7%; ref. 31)
    Colorectal cancer (23)
    Oral squamous cancer (32)
    TranslocationMyeloma (15%-20%; ref. 33)
    Peripheral T-cell lymphoma (rare; ref. 34)
    FGFR4MutationRhabdomyosarcoma (7%-8%; ref. 35)
    Germline SNPCoding SNP: poor prognosis in many cancer types (36)
  • Table 2.

    Ongoing clinical evaluation of anti-FGFR drugs with IC50< 100 nmol against at least one FGFR

    Targets and IC50, nmol/L (if available)
    CompoundFGFR1FGFR2FGFR3FGFR4VEGFR1VEGFR2VEGFR3PDGFR-αPDGFR-βOthers [IC50, nmol/L]Clinical developmentCompany
    MultitargetedTKIs
    TKI258 (dovitinib; ref. 64)891013820027FLT-3 [1]Phase III (RCC)Novartis
    KIT [2]
    CSF-1 [36]
    BIBF1120 (nintedanib; ref. 65)69371086103421135965LCK [16]Phase III (NSCLC, ovarian)Boehringer-Ingelheim
    FLT-3 [26]
    SRC [156]
    LYN [195]
    E3810 (66)17.582.5237.5>1,00072510175525CSF-1 [5]Phase 1 (solid tumors)Ethical Oncology of Science
    KIT [456]
    E7080 (lenvat-inib; ref. 67)462245.25139KIT [100]Phase III (thyroid)Eisai
    BMS582664 (brivanib; ref. 68)148125683802510>6,000Phase III (HCC, CRC)Bristol-Myers Squibb
    ENMD-2076 (69)9371500581656.4FLT-3 [2]Phase II (breast, ovarian)Entremed
    RET [10.4]
    SRC [20.2]
    CSF-1 [24.8]
    Aurora A [14]
    Aurora B [350]
    KIT [120]
    TSU68 (orantinib; ref. 70)1.2μmol/L2.1 μmol/L0.008 μmol/LPhase III (HCC)Taiho Pharmaceutical
    AP24534 (ponatinib; ref. 71)221881.51.1ABL [0.7]Phase II (ALL, CML)Ariad
    SRC [5.4]
    LYN [0.24]
    KIT [12.5]
    Selective TKIs
    AZD4547 (72)0.22.51.816524IGFR [581]Phase II (breast, gastric)AstraZeneca
    BGJ398 (73)0.91.4160Phase 1 (solid tumors)Novartis
    LY2874455 (74)2.82.66.467aPhase 1 (solid tumors)Eli Lilly
    Monoclonal antibodies
    MGFR1877S [cl in icalt rials.gov]Phase I (MM, solid tumors)Genentech
    FGF traps
    HGS1036/FP-1039(75)FGF1Phase I (solid tumors)Human Genomic Sciences
    FGF2
    FGF4

    aSix- to 9-fold cellular and in vivo selectivity on inhibition of FGF- over VEGF-mediated target signaling in mice.

    Abbreviations: ALL, acute lymphoblastic leukemia: CML, chronic myeloid leukemia: CRC, colorectal cancer: FLT-3, Fms-like tyrosine kinase receptor 3: HCC, hepatocellular carcinoma: IGFR, insulin-like growth factor receptor: MM, multiple myeloma: RCC, renal cell carcinoma: STS, soft tissue sarcoma.

    PreviousNext
    Back to top
    Cancer Discovery: 3 (3)
    March 2013
    Volume 3, Issue 3
    • Table of Contents
    • Table of Contents (PDF)
    • About the Cover

    Sign up for alerts

    View this article with LENS

    Open full page PDF
    Article Alerts
    Sign In to Email Alerts with your Email Address
    Email Article

    Thank you for sharing this Cancer Discovery article.

    NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

    Enter multiple addresses on separate lines or separate them with commas.
    Fibroblast Growth Factor Receptor Inhibitors as a Cancer Treatment: From a Biologic Rationale to Medical Perspectives
    (Your Name) has forwarded a page to you from Cancer Discovery
    (Your Name) thought you would be interested in this article in Cancer Discovery.
    CAPTCHA
    This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
    Citation Tools
    Fibroblast Growth Factor Receptor Inhibitors as a Cancer Treatment: From a Biologic Rationale to Medical Perspectives
    Maria Vittoria Dieci, Monica Arnedos, Fabrice Andre and Jean Charles Soria
    Cancer Discov March 1 2013 (3) (3) 264-279; DOI: 10.1158/2159-8290.CD-12-0362

    Citation Manager Formats

    • BibTeX
    • Bookends
    • EasyBib
    • EndNote (tagged)
    • EndNote 8 (xml)
    • Medlars
    • Mendeley
    • Papers
    • RefWorks Tagged
    • Ref Manager
    • RIS
    • Zotero
    Share
    Fibroblast Growth Factor Receptor Inhibitors as a Cancer Treatment: From a Biologic Rationale to Medical Perspectives
    Maria Vittoria Dieci, Monica Arnedos, Fabrice Andre and Jean Charles Soria
    Cancer Discov March 1 2013 (3) (3) 264-279; DOI: 10.1158/2159-8290.CD-12-0362
    del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
    • Tweet Widget
    • Facebook Like
    • Google Plus One

    Jump to section

    • Article
      • Abstract
      • Introduction
      • FGFs and FGFRs in Human Physiology
      • FGF Signaling and Cancer Progression
      • Anti-FGFR Drugs: State of the Art
      • Challenges and Perspectives
      • Conclusions
      • Disclosure of Potential Conflicts of Interest
      • Authors' Contributions
      • References
    • Figures & Data
    • Info & Metrics
    • PDF
    Advertisement

    Related Articles

    Cited By...

    More in this TOC Section

    • Targeting of Checkpoint Receptors within the DNAM1 Axis
    • Anticancer drug repurposing in COVID-19
    • Resistance to KRASG12C Inhibitors
    Show more Review
    • Home
    • Alerts
    • Feedback
    • Privacy Policy
    Facebook   Twitter   LinkedIn   YouTube   RSS

    Articles

    • OnlineFirst
    • Current Issue
    • Past Issues

    Info For

    • Authors
    • Subscribers
    • Advertisers
    • Librarians

    About Cancer Discovery

    • About the Journal
    • Editors
    • Journal Sections
    • Permissions
    • Submit a Manuscript
    AACR logo

    Copyright © 2021 by the American Association for Cancer Research.

    Cancer Discovery
    eISSN: 2159-8290
    ISSN: 2159-8274

    Advertisement