Characterization of the timing and prevalence of receptor tyrosine kinase expression changes in oesophageal carcinogenesis

Paterson, Anna; O’Donovan, Maria; Provenzano, Elena; Murray, Liam; Coleman, Helen; Johnson, Brian T; McManus, Damian; Novelli, Marco; Lovat, Laurence; Fitzgerald, Rebecca C.

doi:10.1002/path.4044

Cited by 35 publications

(36 citation statements)

References 44 publications

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“…Chromosome instability stands out as a hallmark of EA when compared to squamous esophageal cancer and gastric adenocarcinoma 10,91 . Copy number alterations of genes encoding EGFR, ERBB2, MET, and FGFR2 and other receptor tyrosine kinases are also common in EA and show a high degree of redundancy with downstream targets 79,92,93 (Figure 2, Figure 4, Supplementary Table 2). …”

Section: Whole-exome and Whole-genome Analyses Of Eamentioning

confidence: 99%

The Evolving Genomic Landscape of Barrett’s Esophagus and Esophageal Adenocarcinoma

et al. 2017

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We have recently gained unprecedented insight into genetic factors that determine risk for Barrett’s esophagus (BE) and progression to esophageal adenocarcinoma (EA). Next-generation sequencing technologies have allowed us to identify somatic mutations that initiate BE and track genetic changes during development of tumors and invasive cancer. These technologies led to identification of mechanisms of tumorigenesis that challenge the current multi-step model of progression to EA. Newer, cost-effective technologies create opportunities to rapidly translate the analysis of DNA into tools that can identify patients with BE at high risk for cancer, detect dysplastic lesions at earlier stages, and uncover mechanisms of carcinogenesis.

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Section: Whole-exome and Whole-genome Analyses Of Eamentioning

confidence: 99%

The Evolving Genomic Landscape of Barrett’s Esophagus and Esophageal Adenocarcinoma

et al. 2017

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“…In the two main histotypes of esophageal cancer—esophageal (Barrett's) adenocarcinomas (EACs) and esophageal squamous cell carcinomas (ESCCs)—gene amplification and/or protein (over)expression of the RTKs EGFR and HER2 are discussed as prognostic markers and as therapeutic targets . As such, ESCCs predominantly show alterations of EGFR, whereas EACs frequently show HER2 gene amplification and protein overexpression, as shown by fluorescence in situ hybridization and/or immunohistochemistry (IHC) in the majority of studies . This does not preclude that some ESCCs show HER2 or some EACs show EGFR protein overexpression.…”

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confidence: 99%

“…This does not preclude that some ESCCs show HER2 or some EACs show EGFR protein overexpression. Far less is known about HER3 protein expression in esophageal cancers, except two studies showing 45–50% positivity for HER3 expression in ESCCs and two recent studies reporting 87% or negligible HER3 positivity in EACs.…”

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confidence: 99%

“…In view of their prominent role in cancer cell biology and (over‐)expression in substantial numbers of esophageal cancers, EGFR and HER2 represent valuable therapeutic targets for ESCCs and/or EACs . Several preclinical studies addressed EGFR and HER2 inhibition in esophageal cancer cell lines, including EGFR‐targeting TKIs, such as erlotinib or gefitinib, the dual EGFR‐ and HER2‐targeting TKI lapatinib as well as the HER2‐targeting mAB trastuzumab .…”

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EGFR, HER2 and HER3 dimerization patterns guide targeted inhibition in two histotypes of esophageal cancer

Fichter

Timme

Braun

et al. 2014

Intl Journal of Cancer

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Receptor tyrosine kinases (RTKs) are in the focus of targeted therapy for epithelial tumors. Our study addressed the role of EGFR, HER2 and HER3 expression and dimerization in esophageal cancers in situ and in vitro in the context of therapeutic EGFR and HER2 inhibitors. In archival pretreatment biopsies of esophageal carcinomas (n 5 110), EGFR was preferentially expressed in esophageal squamous cell carcinomas (ESCCs) (22.4%; p 5 0.088) and HER2 (34.4%; p < 0.001) with HER3 (91.5%; p < 0.001) in esophageal (Barrett's) adenocarcinomas (EACs). In situ proximity ligation assays revealed mainly EGFR and HER2 homodimers in ESCC and EAC cases, respectively. However, EAC cases also exhibited HER2/HER3 heterodimers. In vitro ESCC (OE21) cells displayed a significant response to erlotinib, gefitinib and lapatinib, with loss of AKT phosphorylation, G0/G1 cell cycle arrest and induction of apoptosis. In EAC cells (OE19, OE33 and SK-GT-4), lapatinib was similarly effective in strongly HER2-positive (mainly HER2 homodimers and some HER2/EGFR heterodimers) OE19 and OE33 cells. The HER2-targeting antibodies (trastuzumab and pertuzumab) given alone were largely ineffective in ESCC and EAC cells. However, both antibodies significantly induced antibody-dependent cellular cytotoxicity in EAC (OE19 and OE33) cells upon co-culture with peripheral blood mononuclear cells. The study reveals that overexpression of EGFR and HER2 predominantly results in homodimers in ESCCs and EACs, respectively. Still, some EACs also show HER2 dimerization plasticity, e.g., with HER3. Such RTK dimerization patterns affect responses to EGFR and HER2 targeting inhibitors in ESCC and EAC cells in vitro and hence may influence future prediction for particularly HER2-targeting inhibitors in EACs.Receptor tyrosine kinases (RTKs) of the EGFR family are involved in development and progression of several epithelial tumors and hence represent therapeutic targets for inhibition by small-molecule tyrosine kinase inhibitors (TKIs) or humanized monoclonal antibodies (mABs) in advanced lung, colorectal, breast and gastric cancer patients.1,2 Thus far, RTK gene amplification or protein expression and alterations of RTK-associated downstream signaling molecules are considered as important factors predicting the response to RTK inhibitors in such epithelial cancer patients. 3In the two main histotypes of esophageal cancer 3-6 -esophageal (Barrett's) adenocarcinomas (EACs) and esophageal squamous cell carcinomas (ESCCs)-gene amplification and/or protein (over)expression of the RTKs EGFR and

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“…MET receptor overexpression, copy number gain or amplification has been associated with a more aggressive phenotype and diminished survival in multiple retrospective patient series. [29, 31, 35-39] In vitro , MET-amplified GEC cells are acutely sensitive to HGF/MET pathway blockade [40, 41]. …”

Section: Introductionmentioning

confidence: 99%

HGF/MET-directed therapeutics in gastroesophageal cancer: a review of clinical and biomarker development

Hack¹,

Bruey²,

Koeppen³

2014

Oncotarget

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Aberrant activation of the HGF/MET signaling axis has been strongly implicated in the malignant transformation and progression of gastroesophageal cancer (GEC). MET receptor overexpression in tumor samples from GEC patients has been consistently correlated with an aggressive metastatic phenotype and poor prognosis. In preclinical GEC models, abrogation of HGF/MET signaling has been shown to induce tumor regression as well as inhibition of metastatic dissemination. Promising clinical results in patient subsets in which MET is overexpressed have spurned several randomized studies of HGF/MET-directed agents, including two pivotal global Phase III trials. Available data highlight the need for predictive biomarkers in order to select patients most likely to benefit from HGF/MET inhibition. In this review, we discuss the current knowledge of mechanisms of MET activation in GEC, the current status of the clinical evaluation of MET-targeted therapies in GEC, characteristics of ongoing randomized GEC trials and the associated efforts to identify and validate biomarkers. We also discuss the considerations and challenges for HGF/MET inhibitor drug development in the GEC setting.

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Characterization of the timing and prevalence of receptor tyrosine kinase expression changes in oesophageal carcinogenesis

Cited by 35 publications

References 44 publications

The Evolving Genomic Landscape of Barrett’s Esophagus and Esophageal Adenocarcinoma

The Evolving Genomic Landscape of Barrett’s Esophagus and Esophageal Adenocarcinoma

EGFR, HER2 and HER3 dimerization patterns guide targeted inhibition in two histotypes of esophageal cancer

HGF/MET-directed therapeutics in gastroesophageal cancer: a review of clinical and biomarker development

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