An FGFR3 Autocrine Loop Sustains Acquired Resistance to Trastuzumab in Gastric Cancer Patients

G. Piro, C. Carbone, Ivana Cataldo, Federica Di Nicolantonio, Simone Giacopuzzi, G. Aprile, F. Simionato, F. Boschi, Marco Zanotto, Maria M. Mina, R. Santoro, valeria merz , Andrea Sbarbati, Giovanni de Manzoni, Aldo Scarpa, Giampolo Tortora, D. Melisi

Research output: Contribution to journalArticle

Abstract

Purpose: The majority of gastric cancer patients who achieve
an initial response to trastuzumab-based regimens develop
resistance within 1 year of treatment. This study was aimed
at identifying the molecular mechanisms responsible for
resistance.
Experimental Design: A HER2þ-trastuzumab sensitive NCIN87
gastric cancer orthotopic nude mouse model was treated
with trastuzumab until resistance emerged. Differentially
expressed transcripts between trastuzumab-resistant and sensitive
gastric cancer cell lines were annotated for functional
interrelatedness by Ingenuity Pathway Analysis software.
Immunohistochemical analyses were performed in pretreatment
versus posttreatment biopsies from gastric cancer
patients receiving trastuzumab-based treatments. All statistical
tests were two-sided.
Results: Four NCI-N87 trastuzumab-resistant (N87-TR) cell
lines were established. Microarray analysis showed HER2 downregulation,
induction of epithelial-to-mesenchymal transition,
and indicated fibroblast growth factor receptor 3 (FGFR3) as one
of the top upregulated genes in N87-TR cell lines. In vitro, N87-TR
cell lines demonstrated a higher sensitivity than did trastuzumabsensitive
parental cells to the FGFR3 inhibitor dovitinib, which
reduced expression of pAKT, ZEB1, and cell migration. Oral
dovitinib significantly (P ¼ 0.0006) reduced tumor burden and
prolonged mice survival duration in N87-TR mouse models. A
higher expression of FGFR3, phosphorylated AKT, and ZEB1 were
observed in biopsies from patients progressing under trastuzumab-
based therapies if compared with matched pretreatment
biopsies.
Conclusions: This study identified the FGFR3/AKT axis as an
escape pathway responsible for trastuzumab resistance in gastric
cancer, thus indicating the inhibition of FGFR3 as a potential
strategy to modulate this resistance.
Original languageEnglish
JournalClinical Cancer Research
Publication statusPublished - 2016

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Receptor, Fibroblast Growth Factor, Type 3
Stomach Neoplasms
Trastuzumab
Biopsy
Cell Line
Epithelial-Mesenchymal Transition
Microarray Analysis
Tumor Burden
Nude Mice
Cell Movement
Neoplasms
Stomach
Research Design
Therapeutics
Down-Regulation
Software

Cite this

An FGFR3 Autocrine Loop Sustains Acquired Resistance to Trastuzumab in Gastric Cancer Patients. / Piro, G.; Carbone, C.; Cataldo, Ivana; Di Nicolantonio, Federica; Giacopuzzi, Simone; Aprile, G.; Simionato, F.; Boschi, F.; Zanotto, Marco; Mina, Maria M.; Santoro, R.; merz , valeria; Sbarbati, Andrea; de Manzoni, Giovanni; Scarpa, Aldo; Tortora, Giampolo; Melisi, D.

In: Clinical Cancer Research, 2016.

Research output: Contribution to journalArticle

Piro, G, Carbone, C, Cataldo, I, Di Nicolantonio, F, Giacopuzzi, S, Aprile, G, Simionato, F, Boschi, F, Zanotto, M, Mina, MM, Santoro, R, merz , V, Sbarbati, A, de Manzoni, G, Scarpa, A, Tortora, G & Melisi, D 2016, 'An FGFR3 Autocrine Loop Sustains Acquired Resistance to Trastuzumab in Gastric Cancer Patients', Clinical Cancer Research.
Piro, G. ; Carbone, C. ; Cataldo, Ivana ; Di Nicolantonio, Federica ; Giacopuzzi, Simone ; Aprile, G. ; Simionato, F. ; Boschi, F. ; Zanotto, Marco ; Mina, Maria M. ; Santoro, R. ; merz , valeria ; Sbarbati, Andrea ; de Manzoni, Giovanni ; Scarpa, Aldo ; Tortora, Giampolo ; Melisi, D. / An FGFR3 Autocrine Loop Sustains Acquired Resistance to Trastuzumab in Gastric Cancer Patients. In: Clinical Cancer Research. 2016.
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abstract = "Purpose: The majority of gastric cancer patients who achievean initial response to trastuzumab-based regimens developresistance within 1 year of treatment. This study was aimedat identifying the molecular mechanisms responsible forresistance.Experimental Design: A HER2{\th}-trastuzumab sensitive NCIN87gastric cancer orthotopic nude mouse model was treatedwith trastuzumab until resistance emerged. Differentiallyexpressed transcripts between trastuzumab-resistant and sensitivegastric cancer cell lines were annotated for functionalinterrelatedness by Ingenuity Pathway Analysis software.Immunohistochemical analyses were performed in pretreatmentversus posttreatment biopsies from gastric cancerpatients receiving trastuzumab-based treatments. All statisticaltests were two-sided.Results: Four NCI-N87 trastuzumab-resistant (N87-TR) celllines were established. Microarray analysis showed HER2 downregulation,induction of epithelial-to-mesenchymal transition,and indicated fibroblast growth factor receptor 3 (FGFR3) as oneof the top upregulated genes in N87-TR cell lines. In vitro, N87-TRcell lines demonstrated a higher sensitivity than did trastuzumabsensitiveparental cells to the FGFR3 inhibitor dovitinib, whichreduced expression of pAKT, ZEB1, and cell migration. Oraldovitinib significantly (P ¼ 0.0006) reduced tumor burden andprolonged mice survival duration in N87-TR mouse models. Ahigher expression of FGFR3, phosphorylated AKT, and ZEB1 wereobserved in biopsies from patients progressing under trastuzumab-based therapies if compared with matched pretreatmentbiopsies.Conclusions: This study identified the FGFR3/AKT axis as anescape pathway responsible for trastuzumab resistance in gastriccancer, thus indicating the inhibition of FGFR3 as a potentialstrategy to modulate this resistance.",
author = "G. Piro and C. Carbone and Ivana Cataldo and {Di Nicolantonio}, Federica and Simone Giacopuzzi and G. Aprile and F. Simionato and F. Boschi and Marco Zanotto and Mina, {Maria M.} and R. Santoro and valeria merz and Andrea Sbarbati and {de Manzoni}, Giovanni and Aldo Scarpa and Giampolo Tortora and D. Melisi",
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TY - JOUR

T1 - An FGFR3 Autocrine Loop Sustains Acquired Resistance to Trastuzumab in Gastric Cancer Patients

AU - Piro, G.

AU - Carbone, C.

AU - Cataldo, Ivana

AU - Di Nicolantonio, Federica

AU - Giacopuzzi, Simone

AU - Aprile, G.

AU - Simionato, F.

AU - Boschi, F.

AU - Zanotto, Marco

AU - Mina, Maria M.

AU - Santoro, R.

AU - merz , valeria

AU - Sbarbati, Andrea

AU - de Manzoni, Giovanni

AU - Scarpa, Aldo

AU - Tortora, Giampolo

AU - Melisi, D.

PY - 2016

Y1 - 2016

N2 - Purpose: The majority of gastric cancer patients who achievean initial response to trastuzumab-based regimens developresistance within 1 year of treatment. This study was aimedat identifying the molecular mechanisms responsible forresistance.Experimental Design: A HER2þ-trastuzumab sensitive NCIN87gastric cancer orthotopic nude mouse model was treatedwith trastuzumab until resistance emerged. Differentiallyexpressed transcripts between trastuzumab-resistant and sensitivegastric cancer cell lines were annotated for functionalinterrelatedness by Ingenuity Pathway Analysis software.Immunohistochemical analyses were performed in pretreatmentversus posttreatment biopsies from gastric cancerpatients receiving trastuzumab-based treatments. All statisticaltests were two-sided.Results: Four NCI-N87 trastuzumab-resistant (N87-TR) celllines were established. Microarray analysis showed HER2 downregulation,induction of epithelial-to-mesenchymal transition,and indicated fibroblast growth factor receptor 3 (FGFR3) as oneof the top upregulated genes in N87-TR cell lines. In vitro, N87-TRcell lines demonstrated a higher sensitivity than did trastuzumabsensitiveparental cells to the FGFR3 inhibitor dovitinib, whichreduced expression of pAKT, ZEB1, and cell migration. Oraldovitinib significantly (P ¼ 0.0006) reduced tumor burden andprolonged mice survival duration in N87-TR mouse models. Ahigher expression of FGFR3, phosphorylated AKT, and ZEB1 wereobserved in biopsies from patients progressing under trastuzumab-based therapies if compared with matched pretreatmentbiopsies.Conclusions: This study identified the FGFR3/AKT axis as anescape pathway responsible for trastuzumab resistance in gastriccancer, thus indicating the inhibition of FGFR3 as a potentialstrategy to modulate this resistance.

AB - Purpose: The majority of gastric cancer patients who achievean initial response to trastuzumab-based regimens developresistance within 1 year of treatment. This study was aimedat identifying the molecular mechanisms responsible forresistance.Experimental Design: A HER2þ-trastuzumab sensitive NCIN87gastric cancer orthotopic nude mouse model was treatedwith trastuzumab until resistance emerged. Differentiallyexpressed transcripts between trastuzumab-resistant and sensitivegastric cancer cell lines were annotated for functionalinterrelatedness by Ingenuity Pathway Analysis software.Immunohistochemical analyses were performed in pretreatmentversus posttreatment biopsies from gastric cancerpatients receiving trastuzumab-based treatments. All statisticaltests were two-sided.Results: Four NCI-N87 trastuzumab-resistant (N87-TR) celllines were established. Microarray analysis showed HER2 downregulation,induction of epithelial-to-mesenchymal transition,and indicated fibroblast growth factor receptor 3 (FGFR3) as oneof the top upregulated genes in N87-TR cell lines. In vitro, N87-TRcell lines demonstrated a higher sensitivity than did trastuzumabsensitiveparental cells to the FGFR3 inhibitor dovitinib, whichreduced expression of pAKT, ZEB1, and cell migration. Oraldovitinib significantly (P ¼ 0.0006) reduced tumor burden andprolonged mice survival duration in N87-TR mouse models. Ahigher expression of FGFR3, phosphorylated AKT, and ZEB1 wereobserved in biopsies from patients progressing under trastuzumab-based therapies if compared with matched pretreatmentbiopsies.Conclusions: This study identified the FGFR3/AKT axis as anescape pathway responsible for trastuzumab resistance in gastriccancer, thus indicating the inhibition of FGFR3 as a potentialstrategy to modulate this resistance.

M3 - Article

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

ER -