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

Abstract

Background:Gastric cancer (GC) is a leading cause of cancer deaths worldwide. Since the approval of trastuzumab, targeted therapies are emerging as promising treatment options for the disease. This study aimed to explore the molecular segmentation of several known therapeutics targets, human epidermal growth factor receptor 2 (HER2), MET and fibroblast growth factor receptor 2 (FGFR2), within GC using clinically approved or investigational kits and scoring criteria. Knowledge of how these markers are segmented in the same cohort of GC patients could improve future clinical trial designs.Methods:Using immunohistochemistry (IHC) and FISH methods, overexpression and amplification of HER2, FGFR2 and MET were profiled in a cohort of Chinese GC samples. The correlations between anti-tumour sensitivity and the molecular segments of HER2, MET and FGFR2 alterations were further tested in a panel of GC cell lines and the patient-derived GC xenograft (PDGCX) model using the targeted inhibitors.Results:Of 172 GC patients, positivity for HER2, MET and FGFR2 alternations was found in 23 (13.4%), 21 (12.2%) and 9 (5.2%) patients, respectively. Positivity for MET was found in 3 of 23 HER2-positive GC patients. Co-positivity for FGFR2 and MET was found in 1 GC patient, and amplification of the two genes was found in different tumour cells. Our study in a panel of GC cell lines showed that in most cell lines, amplification or high expression of a particular molecular marker was mutually exclusive and in vitro sensitivity to the targeted agents lapatinib, PD173074 and crizotinib was only observed in cell lines with the corresponding high expression of the drugs' target protein. SGC031, an MET-positive PDGCX mouse model, responded to crizotinib but not to lapatinib or PD173074.Conclusions:Human epidermal growth factor receptor 2, MET and FGFR2 oncogenic driver alterations (gene amplification and overexpression) occur in three largely distinct molecular segments in GC. A significant proportion of HER2-negative patients may potentially benefit from MET- or FGFR2-targeted therapies.

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

“…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.…”

“…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.…”

“…[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.…”

“…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.…”

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

“…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.…”