Preclinical evidence of multiple mechanisms underlying trastuzumab resistance in gastric cancer

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

HER2-positive advanced gastric cancer patients frequently develop resistance to trastuzumab through mechanisms still poorly understood. In breast cancer, other members of the HER-family are known to be involved in trastuzumab-resistance, as is overexpression of the scaffold protein IQGAP1. In the present work, we investigated acquired resistance to trastuzumab in gastric cancer experimental models. Trastuzumab-resistant (HR) subclones derived from 3 HER2-overexpressing gastric cancer cells were generated and characterized for alterations in HER2- signaling mechanisms by next-generation sequencing, immunohistochemical, western blot and qRT-PCR techniques, and molecular modeling analysis. All subclones showed a reduced growth rate with respect to parental cell lines but each had a different resistance mechanism. In NCI N87 HR cells, characterized by a marked increase in HER2-signaling pathways with respect to the parental cell line, trastuzumab sensitivity was restored when IQGAP1 expression was silenced. AKG HR subclone showed higher HER3 protein expression than the parental line. High nuclear HER4 levels were observed in KKP HR cells. In conclusion, our study revealed that high IQGAP1 expression leads to resistance to trastuzumab in gastric cancer. Furthermore, 2 new mutations of the HER2 gene that may be involved in acquired resistance were identified in AKG HR and KKP HR subclones.

Original languageEnglish
Pages (from-to)18424-18439
Number of pages16
JournalOncotarget
Volume7
Issue number14
DOIs
Publication statusPublished - 2016

Fingerprint

Stomach Neoplasms
erbB-2 Genes
Cell Line
Trastuzumab
Theoretical Models
Western Blotting
Breast Neoplasms
Polymerase Chain Reaction
Mutation
Growth
Proteins

Keywords

  • Gastric cancer
  • HER family receptors
  • HER signaling pathways
  • IQGAP1
  • Trastuzumab resistance

ASJC Scopus subject areas

  • Oncology

Cite this

Preclinical evidence of multiple mechanisms underlying trastuzumab resistance in gastric cancer. / Arienti, Chiara; Zanoni, Michele; Pignatta, Sara; Del Rio, Alberto; Carloni, Silvia; Tebaldi, Michela; Tedaldi, Gianluca; Tesei, Anna.

In: Oncotarget, Vol. 7, No. 14, 2016, p. 18424-18439.

Research output: Contribution to journalArticle

@article{2ba2652c32e1483d810e2381bab13cfd,
title = "Preclinical evidence of multiple mechanisms underlying trastuzumab resistance in gastric cancer",
abstract = "HER2-positive advanced gastric cancer patients frequently develop resistance to trastuzumab through mechanisms still poorly understood. In breast cancer, other members of the HER-family are known to be involved in trastuzumab-resistance, as is overexpression of the scaffold protein IQGAP1. In the present work, we investigated acquired resistance to trastuzumab in gastric cancer experimental models. Trastuzumab-resistant (HR) subclones derived from 3 HER2-overexpressing gastric cancer cells were generated and characterized for alterations in HER2- signaling mechanisms by next-generation sequencing, immunohistochemical, western blot and qRT-PCR techniques, and molecular modeling analysis. All subclones showed a reduced growth rate with respect to parental cell lines but each had a different resistance mechanism. In NCI N87 HR cells, characterized by a marked increase in HER2-signaling pathways with respect to the parental cell line, trastuzumab sensitivity was restored when IQGAP1 expression was silenced. AKG HR subclone showed higher HER3 protein expression than the parental line. High nuclear HER4 levels were observed in KKP HR cells. In conclusion, our study revealed that high IQGAP1 expression leads to resistance to trastuzumab in gastric cancer. Furthermore, 2 new mutations of the HER2 gene that may be involved in acquired resistance were identified in AKG HR and KKP HR subclones.",
keywords = "Gastric cancer, HER family receptors, HER signaling pathways, IQGAP1, Trastuzumab resistance",
author = "Chiara Arienti and Michele Zanoni and Sara Pignatta and {Del Rio}, Alberto and Silvia Carloni and Michela Tebaldi and Gianluca Tedaldi and Anna Tesei",
year = "2016",
doi = "10.18632/oncotarget.7575",
language = "English",
volume = "7",
pages = "18424--18439",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals LLC",
number = "14",

}

TY - JOUR

T1 - Preclinical evidence of multiple mechanisms underlying trastuzumab resistance in gastric cancer

AU - Arienti, Chiara

AU - Zanoni, Michele

AU - Pignatta, Sara

AU - Del Rio, Alberto

AU - Carloni, Silvia

AU - Tebaldi, Michela

AU - Tedaldi, Gianluca

AU - Tesei, Anna

PY - 2016

Y1 - 2016

N2 - HER2-positive advanced gastric cancer patients frequently develop resistance to trastuzumab through mechanisms still poorly understood. In breast cancer, other members of the HER-family are known to be involved in trastuzumab-resistance, as is overexpression of the scaffold protein IQGAP1. In the present work, we investigated acquired resistance to trastuzumab in gastric cancer experimental models. Trastuzumab-resistant (HR) subclones derived from 3 HER2-overexpressing gastric cancer cells were generated and characterized for alterations in HER2- signaling mechanisms by next-generation sequencing, immunohistochemical, western blot and qRT-PCR techniques, and molecular modeling analysis. All subclones showed a reduced growth rate with respect to parental cell lines but each had a different resistance mechanism. In NCI N87 HR cells, characterized by a marked increase in HER2-signaling pathways with respect to the parental cell line, trastuzumab sensitivity was restored when IQGAP1 expression was silenced. AKG HR subclone showed higher HER3 protein expression than the parental line. High nuclear HER4 levels were observed in KKP HR cells. In conclusion, our study revealed that high IQGAP1 expression leads to resistance to trastuzumab in gastric cancer. Furthermore, 2 new mutations of the HER2 gene that may be involved in acquired resistance were identified in AKG HR and KKP HR subclones.

AB - HER2-positive advanced gastric cancer patients frequently develop resistance to trastuzumab through mechanisms still poorly understood. In breast cancer, other members of the HER-family are known to be involved in trastuzumab-resistance, as is overexpression of the scaffold protein IQGAP1. In the present work, we investigated acquired resistance to trastuzumab in gastric cancer experimental models. Trastuzumab-resistant (HR) subclones derived from 3 HER2-overexpressing gastric cancer cells were generated and characterized for alterations in HER2- signaling mechanisms by next-generation sequencing, immunohistochemical, western blot and qRT-PCR techniques, and molecular modeling analysis. All subclones showed a reduced growth rate with respect to parental cell lines but each had a different resistance mechanism. In NCI N87 HR cells, characterized by a marked increase in HER2-signaling pathways with respect to the parental cell line, trastuzumab sensitivity was restored when IQGAP1 expression was silenced. AKG HR subclone showed higher HER3 protein expression than the parental line. High nuclear HER4 levels were observed in KKP HR cells. In conclusion, our study revealed that high IQGAP1 expression leads to resistance to trastuzumab in gastric cancer. Furthermore, 2 new mutations of the HER2 gene that may be involved in acquired resistance were identified in AKG HR and KKP HR subclones.

KW - Gastric cancer

KW - HER family receptors

KW - HER signaling pathways

KW - IQGAP1

KW - Trastuzumab resistance

UR - http://www.scopus.com/inward/record.url?scp=84975496705&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84975496705&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.7575

DO - 10.18632/oncotarget.7575

M3 - Article

VL - 7

SP - 18424

EP - 18439

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 14

ER -