HER2, MET and FGFR2 oncogenic driver alterations define distinct molecular segments for targeted therapies in gastric carcinoma

Liu, Yao-Bin; Shen, Danhong; Yin, Xiaolu; Gavine, Paul R.; Zhang, T; Su, Xinying; Zhan, Ping; Xu, Yanping; Lv, Jing; Qian, Jun; Liu, C; Sun, Yun-Fan; Zhou, Qian; Zhang, J; Gu, Yi; Ni, Xiaoqing

doi:10.1038/bjc.2014.61

Cited by 96 publications

(88 citation statements)

References 39 publications

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“…Furthermore, 26% (24 of 93) of the amplifications were amplification of one of four genes (ERBB2, FGFR2, MET, and EGFR) that encode a RTK. The frequencies of these gene amplifications were not significantly different from those previously reported for ERBB2, FGFR2, 9,10,12,14 MET, 6,7,14,15 and EGFR. 6,20 It is intriguing that, except for case 7, RTK gene amplification occurred in a mutually exclusive manner.…”

Section: Discussioncontrasting

confidence: 76%

“…8,9 In preclinical studies, cells with amplified FGFR2 or MET showed overexpression of their respective proteins, and inhibitors to these receptors were shown to effectively block their downstream signal transduction and induce apoptosis. [10][11][12][13][14] At present, apart from ERBB2 targeting, approaches for targeting MET and FGFR2 are the most clinically advanced of prospective targeted therapy. However, the prevalence of amplification of each of these genes, as assessed by oligonucleotide array comparative genetic hybridization, real-time PCR, fluorescence in situ hybridization (FISH), or silver in situ hybridization is low, ie, from 2 to 5% for FGFR2, 9,10,12,14 and from 2 to 8% for MET, respectively.…”

mentioning

confidence: 99%

“…[10][11][12][13][14] At present, apart from ERBB2 targeting, approaches for targeting MET and FGFR2 are the most clinically advanced of prospective targeted therapy. However, the prevalence of amplification of each of these genes, as assessed by oligonucleotide array comparative genetic hybridization, real-time PCR, fluorescence in situ hybridization (FISH), or silver in situ hybridization is low, ie, from 2 to 5% for FGFR2, 9,10,12,14 and from 2 to 8% for MET, respectively. 6,7,14,15 Intriguingly, a recent comprehensive genome-wide analysis of copy number alterations using an single nucleotide polymorphism array 13 showed that amplification of FGFR2, EGFR, ERBB2, and MET occurred mutually exclusively and that other genes such as MYC and CCND1 were also amplified in gastric cancer.…”

mentioning

confidence: 99%

“…However, the prevalence of amplification of each of these genes, as assessed by oligonucleotide array comparative genetic hybridization, real-time PCR, fluorescence in situ hybridization (FISH), or silver in situ hybridization is low, ie, from 2 to 5% for FGFR2, 9,10,12,14 and from 2 to 8% for MET, respectively. 6,7,14,15 Intriguingly, a recent comprehensive genome-wide analysis of copy number alterations using an single nucleotide polymorphism array 13 showed that amplification of FGFR2, EGFR, ERBB2, and MET occurred mutually exclusively and that other genes such as MYC and CCND1 were also amplified in gastric cancer. When considering promising targets of molecular therapy, the apparently low prevalence of these gene amplifications in gastric cancer makes selection of the right set of patients that can benefit from targeted therapy a difficult challenge.…”

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confidence: 99%

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Semi-comprehensive analysis of gene amplification in gastric cancers using multiplex ligation-dependent probe amplification and fluorescence in situ hybridization

et al. 2015

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The prognosis of patients with gastric carcinomas at an advanced stage still remains dismal, and therefore novel therapeutic modalities are urgently needed. Since the successful targeting of amplified ERBB2 with a humanized monoclonal antibody, the amplified genes of other receptor tyrosine kinases such as EGFR, FGFR2, and MET, as well as those of other cell regulator genes, are being considered as candidate targets of molecular therapy. The aim of the present study was to determine the amplification status of 26 genes, which are frequently amplified in solid cancers, in advanced gastric cancers. A total of 93 formalin-fixed and paraffin-embedded advanced gastric cancer tissues were examined by multiple ligation-dependent probe amplification, and 32 cases with 'gain' or 'amplified' status of 16 genes were further examined for the respective gene amplification by fluorescence in situ hybridization (FISH) and for the respective protein overexpression by immunohistochemistry. The frequencies of gene amplifications in advanced gastric cancers were as follows: ERBB2 (13 cases, 14%), FGFR2 (7 cases, 8%), MYC (7 cases, 8%), TOP2A (7 cases, 8%), MET (4 cases, 4%), MDM2 (4 cases, 4%), CCND1 (3 cases, 3%), FGF10 (2 cases, 3%), and EGFR (1 case, 1%). Amplification of the receptor tyrosine kinases genes occurred in a mutually exclusive manner except for one tumor in which ERBB2 and FGFR2 were both amplified but in different cancer cells. Co-amplification of ERBB2 and MYC, and EGFR and CCND1, in single nuclei but on different amplicons, was confirmed in one case each. Attempts at correlating the FISH status with the immunohistochemical staining pattern showed variable results from complete concordance to no correlation. In conclusion, combination of multiple ligation-dependent probe amplification and FISH analysis is a feasible approach for obtaining the semi-comprehensive genetic information that is necessary for personalized molecular targeted therapy.

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Section: Discussioncontrasting

confidence: 76%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Semi-comprehensive analysis of gene amplification in gastric cancers using multiplex ligation-dependent probe amplification and fluorescence in situ hybridization

et al. 2015

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“…For example, recent IHC studies performed on gastric tumour samples have reported cMET over-expression in 4-63% of cases [72][73][74][75][76][77] and various studies performed in ovarian cancer estimate high expression of cMET to be present in 11-68 % of cases [30,22,23,26,25] (Table 1). The majority of the estimates above come from IHC studies, using a number of different antibodies, but no consensus on scoring criteria yet exists, nor whether cytoplasmic or membranous staining for cMET is important.…”

Section: Ihc For Cmetmentioning

confidence: 99%

The Therapeutic Potential of Targeting the HGF/cMET Axis in Ovarian Cancer

Moran-Jones

2016

Mol Diagn Ther

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Survival rates for ovarian cancer have remained relatively stable for the past two decades, despite advances in surgical techniques and cytotoxic chemotherapeutics, indicating a requirement for better therapies. One pathway currently proposed for targeting is the HGF/cMET pathway. Up-regulated in a number of tumour types, cMET is a tyrosine kinase receptor expressed on epithelial cells. In ovarian cancer, it has been identified as highly expressed in the four major subtypes, with expression estimates ranging from 11-68% of cases. HGF, the only known ligand for cMET, is found at high levels in both serum and ascites in women with ovarian cancer, and proposed to induce both migration and metastasis. However, clinically validated biomarkers are not yet available for either HGF or cMET, preventing a clear understanding of the true rate of over-expression, or its correlation with prognosis.

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Effects of trastuzumab and afatinib on kinase activity in gastric cancer cell lines

et al. 2018

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The molecular mechanism of action of the HER2‐targeted antibody trastuzumab is only partially understood, and the direct effects of trastuzumab on the gastric cancer signaling network are unknown. In this study, we compared the molecular effect of trastuzumab and the HER kinase inhibitor afatinib on the receptor tyrosine kinase (RTK) network and the downstream‐acting intracellular kinases in gastric cancer cell lines. The molecular effects of trastuzumab and afatinib on the phosphorylation of 49 RTKs and 43 intracellular kinase phosphorylation sites were investigated in three gastric cancer cell lines (NCI‐N87, MKN1, and MKN7) using proteome profiling. To evaluate these effects, data were analyzed using mixed models and clustering. Moreover, proliferation assays were performed. Our comprehensive quantitative analysis of kinase activity in gastric cancer cell lines indicates that trastuzumab and afatinib selectively influenced the HER family RTKs. The effects of trastuzumab differed between cell lines, depending on the presence of activated HER2. The effects of trastuzumab monotherapy were not transduced to the intracellular kinase network. Afatinib alone or in combination with trastuzumab influenced HER kinases in all cell lines; that is, the effects of monotherapy and combination therapy were transduced to the intracellular kinase network. These results were confirmed by proliferation analysis. Additionally, the MET‐amplified cell line Hs746T was identified as afatinib nonresponder. The dependence of the effect of trastuzumab on the presence of activated HER2 might explain the clinical nonresponse of some patients who are routinely tested for HER2 expression and gene amplification in the clinic but not for HER2 activation. The consistent effects of afatinib on HER RTKs and downstream kinase activation suggest that afatinib might be an effective candidate in the future treatment of patients with gastric cancer irrespective of the presence of activated HER2. However, MET amplification should be taken into account as potential resistance factor.

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HER2, MET and FGFR2 oncogenic driver alterations define distinct molecular segments for targeted therapies in gastric carcinoma

Cited by 96 publications

References 39 publications

Semi-comprehensive analysis of gene amplification in gastric cancers using multiplex ligation-dependent probe amplification and fluorescence in situ hybridization

Semi-comprehensive analysis of gene amplification in gastric cancers using multiplex ligation-dependent probe amplification and fluorescence in situ hybridization

The Therapeutic Potential of Targeting the HGF/cMET Axis in Ovarian Cancer

Effects of trastuzumab and afatinib on kinase activity in gastric cancer cell lines

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