Format

Send to

Choose Destination
Mol Cancer Ther. 2019 Sep 4. pii: molcanther.0455.2019. doi: 10.1158/1535-7163.MCT-19-0455. [Epub ahead of print]

HER-family ligands promote acquired resistance to trastuzumab in gastric cancer.

Author information

1
Cancer Research Program, IMIM, Hospital del Mar-CIBERONC.
2
Cancer Research Program, IMIM (Hospital del Mar Research Institute)-CIBERONC.
3
Cancer research program, IMIM (Institut Hospital del Mar d'Investigacions Mèdiques).
4
Medical Oncology Department, Hospital Del Mar.
5
Pathology, Hospital Del Mar.
6
Cancer Research Program, IMIM.
7
Oncologie Médicale, Institut de Cancérologie et Hématologie et Hématologie Morvan.
8
Radiology Department, Hospital Del Mar.
9
Pathology Department, Hospital Del Mar.
10
Gene Function and Evolution, Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology.
11
Preclinical Development, Symphogen (Denmark).
12
Department of Pathology, University Hospital del Mar.
13
Medical Oncology, Hospital Del Mar.
14
Department of Medical Oncology, Del Mar University Hospital cmontagut@hospitaldelmar.cat.

Abstract

Despite the clinical benefit of trastuzumab, eventually all HER2-amplified gastric cancer tumors develop drug resistance. We aimed to identify molecular mechanisms of acquired resistance to trastuzumab in gastric cancer by using well-established cell-line based preclinical models, as well as samples from HER2-positive gastric cancer patients treated with trastuzumab. We studied trastuzumab resistance in NCI-N87 and OE19, two gastric cancer cell lines that overexpress HER2 receptor and are trastuzumab sensitive. Differences at protein, DNA, and RNA levels between the parental and resistant cells were characterized and functional studies were performed. Paired pre- and post-trastuzumab blood and tissue samples from gastric cancer patients treated with trastuzumab were analyzed. We found that resistant cells were associated with increased activation of MAPK/ERK and PI3K/mTOR pathways driven by SRC activation. Upstream, resistant cells showed increased co-expression of multiple HER-family ligands that allowed for compensatory activation of alternative HER receptors upon HER2 blockade. Simultaneous inhibition of EGFR, HER2, and HER3 by the novel antibody mixture Pan-HER effectively reverted trastuzumab resistance in vitro and in vivo. Similarly, an increase in HER-family ligands was observed in serum and tumor from gastric cancer patients after trastuzumab therapy. We propose that trastuzumab resistance in gastric cancer is mediated by HER-family ligands upregulation that allow a compensatory activation of HER receptors and maintain downstream signaling activation despite trastuzumab therapy. Resistance is reverted by simultaneous inhibition of EGFR, HER2, and HER3 thereby revealing a potential therapeutic strategy to overcome trastuzumab resistance in gastric cancer patients.

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center