Differential Expression of Epidermal Growth Factor Receptor, c-Met, and HER2/neu in Chordoma Compared With 17 Other Malignancies

Weinberger, Paul M.; Yang, Ziwei; Kowalski, Diane; Joe, John K.; Manger, Phillip; Psyrri, Amanda; Sasaki, Clarence T.

doi:10.1001/archotol.131.8.707

Cited by 96 publications

(75 citation statements)

References 20 publications

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“…As it is known that chordomas also express several other tyrosine kinase receptors including c-MET, PDGFR b and KIT, EGFR, Her2/ neu and TrK, which also activate the RAS/RAF/ MEK/ERK pathway, these should be considered candidates for the regulation of brachyury. [28][29][30][31][32] The occurrence of FGFR mutations is well documented in the literature, and these are associated in both neoplasia and developmental syndromes. The mutations implicated in the former include those in endometrial, gastric, urothelial and prostatic cancers, 21,[33][34][35][36][37] and many of the activating FGFR2 and FGFR3 mutations, recently reported in endometrial carcinomas, are identical to germline mutations known to cause syndromes, several of which give rise to skeletal abnormalities including the Apert Syndrome, Beare-Stevenson Syndrome, hypochondroplasia, achondroplasia and the SAD-DAN syndrome (see Supplementary Table 2 based on Catalogue of Somatic Mutations In Cancer (COSMIC).…”

Section: Discussionmentioning

confidence: 99%

Analysis of the fibroblastic growth factor receptor-RAS/RAF/MEK/ERK-ETS2/brachyury signalling pathway in chordomas

et al. 2009

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Chordomas are rare primary malignant bone tumours that derive from notochord precursor cells and express brachyury, a molecule involved in notochord development. Little is known about the genetic events responsible for driving the growth of this tumour, but it is well established that brachyury is regulated through fibroblastic growth factor receptors (FGFRs) through RAS/RAF/MEK/ERK and ETS2 in ascidian, Xenopus and zebrafish, although little is known about its regulation in mammals. The aim of this study was to attempt to identify the molecular genetic events that are responsible for the pathogenesis of chordomas with particular focus on the FGFR signalling pathway on the basis of the evidence in the ascidian and Xenopus models that the expression of brachyury requires the activation of this pathway. Immunohistochemistry showed that 47 of 50 chordomas (94%) expressed at least one of the FGFRs, and western blotting showed phosphorylation of fibroblast growth factor receptor substrate 2 alpha (FRS2a), an adaptor signalling protein, that links FGFR to the RAS/RAF/MEK/ ERK pathway. Screening for mutations in brachyury (all coding exons and promoter), FGFRs 1-4 (previously reported mutations), KRAS (codons 12, 13, 51, 61) and BRAF (exons 11 and 15) failed to show any genetic alterations in 23 chordomas. Fluorescent in situ hybridisation analysis on FGFR4, ETS2 and brachyury failed to show either amplification of these genes, although there was minor allelic gain in brachyury in three tumours, or translocation for ERG and ETS2 loci. The key genetic events responsible for the initiation and progression of chordomas remain to be discovered.

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Section: Discussionmentioning

confidence: 99%

Analysis of the fibroblastic growth factor receptor-RAS/RAF/MEK/ERK-ETS2/brachyury signalling pathway in chordomas

et al. 2009

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“…In this respect, expression of EGFR and MET correlate in multiple malignancies such as chordoma, prostate and ovarian carcinomas, and gastrinoma (25). EGFR has been implicated in HGF-induced hepatocyte proliferation and is required for MET-mediated colon cancer cell invasiveness (26).…”

Section: Introductionmentioning

confidence: 99%

Increased TGF-α as a Mechanism of Acquired Resistance to the Anti-EGFR Inhibitor Cetuximab through EGFR–MET Interaction and Activation of MET Signaling in Colon Cancer Cells

Troiani

Martinelli

Napolitano

et al. 2013

Clinical Cancer Research

133

145

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Purpose: Although cetuximab, an anti-EGF receptor (EGFR) monoclonal antibody, is an effective treatment for patients with KRAS wild-type metastatic colorectal cancer (mCRC), its clinical use is limited by onset of resistance.Experimental Design: We characterized two colorectal cancer models to study the mechanisms of acquired resistance to cetuximab.Results: Following chronic treatment of nude mice bearing cetuximab-sensitive human GEO colon xenografts, cetuximab-resistant GEO (GEO-CR) cells were obtained. In GEO-CR cells, proliferation and survival signals were constitutively active despite EGFR inhibition by cetuximab treatment. Whole gene expression profiling identified a series of genes involved in the hepatocyte growth factor (HGF)-MET-dependent pathways, whichwere upregulated in GEO-CR cells.Furthermore,activated, phosphorylated MET was detected in GEO-CR cells. A second colorectal cancer cell line with acquired resistance to cetuximab was obtained (SW48-CR). Inhibition of MET expression by siRNA restored cetuximab sensitivity in GEO-CR and SW48-CR cells, whereas exogenousactivation ofMETbyHGFstimulationin cetuximab-sensitiveGEOandSW48cells inducedresistance to cetuximab. Treatment of GEO-CR and SW48-CR cells with PHA665752, a selective MET inhibitor, inhibited cell growth, proliferation, and survival signals and impaired cancer cell migration. Overexpression of TGF-a, a specific EGFR ligand, was involved in the acquisition of cetuximab resistance in GEO-CR and SW48-CR cells. In fact, TGF-a overexpression induced the EGFR-MET interaction, with subsequent MET phosphorylation and activation of MET downstream effectors in GEO-CR and SW48-CR cells.Conclusions: These results suggest that overexpression of TGF-a through induction of EGFR-MET interaction contributes to cetuximab resistance in colorectal cancer cells. The combined inhibition of EGFR and MET receptor could represent a strategy for preventing and/or overcoming cetuximab resistance in patients with colorectal cancer.

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“…It has to be underlined that empirical evidence of the potential use of EGFR inhibitors in chordoma patients already existed, indicating that EGFR inhibition in chordoma patients may represent a feasible strategy [1,2]. These sporadic clinical observations have been also corroborated by preliminary data on the possible role of EGFR in chordoma pathogenesis [6].…”

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confidence: 94%

“…Chordoma tends to behave as a low-grade malignancy, exhibiting relentless growth and almost invariably leading to metastatic spread over the years. Whereas proton therapy plays a role in skull base chordomas, systemic treatments have proved substantially ineffective, even though first attempts to understand the underlying driving molecular mechanisms have led to partially successful innovative therapeutic approaches [1][2][3]. Nonetheless, chordoma still remains one of the prototypical orphan cancers, and patients would certainly benefit from a more precise elucidation of its molecular pathogenesis.…”

mentioning

confidence: 99%

“…The main criticism to this new methodology is represented by the assumption that the actual availability of data to generate a strong prior probability is most often unsatisfactory. However, this is why the data shown on chordoma are so important: in fact, the combination of powerful preclinical data with empirical evidence of efficacy, as shown by case reports [1,2], is exactly what is needed to make this approach feasible and to overcome the limitation of rarity. This novel methodological approach to clinical studies in rare cancers does not represent a mere futuristic vision, but represents one of the key tasks of the ongoing European Action Against Rare Cancers [10] as well as a major point of discussion among clinicians focused on rare tumours.…”

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confidence: 99%

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Unveiling the molecular pathogenesis of chordoma: a new paradigm for molecular targeting of rare cancers

Tos

2011

The Journal of Pathology

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Abstract‘Chordoma’ represents orphan sarcoma subtypes in which systemic treatments have so far proved ineffective. Two original papers in the Journal of Pathology have recently elucidated important steps of its molecular oncogenesis. The demonstration of gains of copy number of both T (brachyury homologue) and EGFR (epidermal growth factor receptor) genes in chordoma, as well as of their role in promoting cell proliferation, offers a strong preclinical rationale for exploring the inhibition of their products as a credible therapeutic strategy. When dealing with rare cancers, clinical trials based on a frequency‐based statistical methodology are hardly feasible. To override the limitations of rarity, the clinical community is suggesting the adoption of a Bayesian methodology. The success of innovative clinical trials strongly depends upon the availability of preclinical evidences of efficacy. The papers discussed herein represent good examples of what is actually needed to set up a solid prior probability. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Differential Expression of Epidermal Growth Factor Receptor, c-Met, and HER2/neu in Chordoma Compared With 17 Other Malignancies

Cited by 96 publications

References 20 publications

Analysis of the fibroblastic growth factor receptor-RAS/RAF/MEK/ERK-ETS2/brachyury signalling pathway in chordomas

Analysis of the fibroblastic growth factor receptor-RAS/RAF/MEK/ERK-ETS2/brachyury signalling pathway in chordomas

Increased TGF-α as a Mechanism of Acquired Resistance to the Anti-EGFR Inhibitor Cetuximab through EGFR–MET Interaction and Activation of MET Signaling in Colon Cancer Cells

Unveiling the molecular pathogenesis of chordoma: a new paradigm for molecular targeting of rare cancers

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