198
views
0
recommends
+1 Recommend
0 collections
    16
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      A mechanism of resistance to gefitinib mediated by cellular reprogramming and the acquisition of an FGF2-FGFR1 autocrine growth loop

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Despite initial and often dramatic responses of epidermal growth factor receptor (EGFR)-addicted lung tumors to the EGFR-specific tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, nearly all develop resistance and relapse. To explore novel mechanisms mediating acquired resistance, we employed non-small-cell lung cancer (NSCLC) cell lines bearing activating mutations in EGFR and rendered them resistant to EGFR-specific TKIs through chronic adaptation in tissue culture. In addition to previously observed resistance mechanisms including EGFR-T790M ‘gate-keeper' mutations and MET amplification, a subset of the seven chronically adapted NSCLC cell lines including HCC4006, HCC2279 and H1650 cells exhibited marked induction of fibroblast growth factor (FGF) 2 and FGF receptor 1 (FGFR1) mRNA and protein. Also, adaptation to EGFR-specific TKIs was accompanied by an epithelial to mesenchymal transition (EMT) as assessed by changes in CDH1, VIM, ZEB1 and ZEB2 expression and altered growth properties in Matrigel. In adapted cell lines exhibiting increased FGF2 and FGFR1 expression, measures of growth and signaling, but not EMT, were blocked by FGFR-specific TKIs, an FGF-ligand trap and FGFR1 silencing with RNAi. In parental HCC4006 cells, cell growth was strongly inhibited by gefitinib, although drug-resistant clones progress within 10 days. Combined treatment with gefitinib and AZD4547, an FGFR-specific TKI, prevented the outgrowth of drug-resistant clones. Thus, induction of FGF2 and FGFR1 following chronic adaptation to EGFR-specific TKIs provides a novel autocrine receptor tyrosine kinase-driven bypass pathway in a subset of lung cancer cell lines that are initially sensitive to EGFR-specific TKIs. The findings support FGFR-specific TKIs as potentially valuable additions to existing targeted therapeutic strategies with EGFR-specific TKIs to prevent or delay acquired resistance in EGFR-driven NSCLC.

          Related collections

          Most cited references28

          • Record: found
          • Abstract: found
          • Article: not found

          EGFR mutations and lung cancer.

          Epidermal growth factor receptor (EGFR) is a transmembrane protein with cytoplasmic kinase activity that transduces important growth factor signaling from the extracellular milieu to the cell. Given that more than 60% of non-small cell lung carcinomas (NSCLCs) express EGFR, EGFR has become an important therapeutic target for the treatment of these tumors. Inhibitors that target the kinase domain of EGFR have been developed and are clinically active. More importantly, such tyrosine kinase inhibitors (TKIs) are especially effective in patients whose tumors harbor activating mutations in the tyrosine kinase domain of the EGFR gene. More recent trials have suggested that for advanced NSCLC patients with EGFR mutant tumors, initial therapy with a TKI instead of chemotherapy may be the best choice of treatment. Therefore, mutation testing is mandatory to identify these patients, given that selection based only on clinico-pathologic characteristics is inadequate. We review the role of EGFR mutations in the diagnosis and management of NSCLC.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumors harboring the T790M mutation.

            Patients with epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma develop acquired resistance to EGFR tyrosine kinase inhibitors (TKI) after a median of 10 to 16 months. In half of these cases, a second EGFR mutation, T790M, underlies acquired resistance. We undertook this study to examine the clinical course of patients harboring the T790M mutation following progression on TKI. EGFR-mutant lung cancer patients with acquired resistance to EGFR TKIs were identified as part of a prospective rebiopsy protocol in which postprogression tumor specimens were collected for molecular analysis. Postprogression survival and characteristics of disease progression were compared in patients with and without T790M. We identified T790M in the initial rebiopsy specimens from 58 of 93 patients (62%, 95% CI: 52-72). T790M was more common in biopsies of lung/pleura tissue and lymph nodes than in more distant sites (P = 0.014). Median postprogression survival was 16 months (interquartile range = 9-29 months); patients with T790M had a significantly longer postprogression survival (P = 0.036). Patients without T790M more often progressed in a previously uninvolved organ system (P = 0.014) and exhibited a poorer performance status at time of progression (P = 0.007). Among patients with acquired resistance to EGFR TKIs, the presence of T790M defines a clinical subset with a relatively favorable prognosis and more indolent progression. Knowledge of T790M status is therefore important both for the clinical care of these patients and for the optimal design and interpretation of clinical trials in this setting. ©2010 AACR.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              AZD4547: an orally bioavailable, potent, and selective inhibitor of the fibroblast growth factor receptor tyrosine kinase family.

              The fibroblast growth factor (FGF) signaling axis is increasingly implicated in tumorigenesis and chemoresistance. Several small-molecule FGF receptor (FGFR) kinase inhibitors are currently in clinical development; however, the predominant activity of the most advanced of these agents is against the kinase insert domain receptor (KDR), which compromises the FGFR selectivity. Here, we report the pharmacologic profile of AZD4547, a novel and selective inhibitor of the FGFR1, 2, and 3 tyrosine kinases. AZD4547 inhibited recombinant FGFR kinase activity in vitro and suppressed FGFR signaling and growth in tumor cell lines with deregulated FGFR expression. In a representative FGFR-driven human tumor xenograft model, oral administration of AZD4547 was well tolerated and resulted in potent dose-dependent antitumor activity, consistent with plasma exposure and pharmacodynamic modulation of tumor FGFR. Importantly, at efficacious doses, no evidence of anti-KDR-related effects were observed, confirming the in vivo FGFR selectivity of AZD4547. Taken together, our findings show that AZD4547 is a novel selective small-molecule inhibitor of FGFR with potent antitumor activity against FGFR-deregulated tumors in preclinical models. AZD4547 is under clinical investigation for the treatment of FGFR-dependent tumors.
                Bookmark

                Author and article information

                Journal
                Oncogenesis
                Oncogenesis
                Oncogenesis
                Nature Publishing Group
                2157-9024
                March 2013
                25 March 2013
                1 March 2013
                : 2
                : 3
                : e39
                Affiliations
                [1 ]Department of Craniofacial Biology, School of Dental Medicine, University of Colorado Anschutz Medical Campus , Aurora, CO, USA
                [2 ]Department of Medicine, University of Colorado Anschutz Medical Campus , Aurora, CO, USA
                [3 ]Department of Pediatrics, University of Colorado Anschutz Medical Campus , Aurora, CO, USA
                Author notes
                [* ]Department of Craniofacial Biology, School of Dental Medicine, University of Colorado Denver Anschutz Medical Campus , Mail Stop 8120, PO Box 6511, Aurora, CO 80045, USA. E-mail: Lynn.Heasley@ 123456ucdenver.edu
                Article
                oncsis20134
                10.1038/oncsis.2013.4
                3641357
                23552882
                d39491bb-b306-42ef-9a18-a11a00edffb9
                Copyright © 2013 Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

                History
                : 13 August 2012
                : 23 January 2013
                : 03 February 2013
                Categories
                Original Article

                Oncology & Radiotherapy
                gefitinib,egfr,fgfr1,fgf2,acquired resistance,nsclc
                Oncology & Radiotherapy
                gefitinib, egfr, fgfr1, fgf2, acquired resistance, nsclc

                Comments

                Comment on this article