Activation of HER family members in gastric carcinoma cells mediates resistance to MET inhibition

Corso, Simona; Ghiso, Elena; Cepero, Virna; Sierra, J. Rafael; Migliore, Cristina; Bertotti, Andrea; Trusolino, Livio; Comoglio, Paolo M.; Giordano, Silvia

doi:10.1186/1476-4598-9-121

Cited by 93 publications

(83 citation statements)

References 46 publications

(59 reference statements)

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“…In MET-addicted gastric cancer, activation of HER family members was poorly responsive to MET inhibitor [29]. In HER2-overexpressing breast cancer, the insulin-like growth factor receptor, other human epidermal growth factor receptor family members (EGFR, HER3) and MET overexpression might be critical for treatmentacquired resistance to trastuzumab [30][31][32].…”

Section: Discussionmentioning

confidence: 99%

Expression profiles of HER2, EGFR, MET and FGFR2 in a large cohort of patients with gastric adenocarcinoma

et al. 2014

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Background Some tyrosine kinase receptors (RTKs) play critical roles in gastric cancer progression. Not only trastuzumab, but also several other agents targeting RTKs are being investigated for gastric cancer therapy. However, the simultaneous expression of multiple RTKs, which may interfere with the effectiveness of therapeutic agents, has not been evaluated in a large cohort with gastric adenocarcinoma (GAC). Methods We performed a tissue microarray analysis in 950 patients with GAC who underwent a gastrectomy without preoperative chemotherapy. The protein expressions of HER2, EGFR, MET and FGFR2 were evaluated using immunohistochemistry, and the gene amplifications of HER2, EGFR and MET were examined using dual-color in situ hybridization.Results The frequency of overexpression was 11.8 % for HER2, 23.5 % for EGFR, 24.9 % for MET and 31.1 % for FGFR2. Whereas strong staining for each of the RTKs was heterogeneous, tumors with homogeneously strong staining areas often exhibited gene amplification. Strong EGFR expression was significantly associated with a poor outcome, but no prognostic correlations were observed in other RTKs. The overexpression of single and multiple RTKs was observed in 40.4 and 22.7 % of the cases, respectively. HER2, EGFR, MET and FGFR2 predominance was observed in 10.1, 13.9, 16.1 and 22.9 % of the GACs, respectively. Conclusions Approximately two-thirds of patients with GAC exhibited the expression of at least one RTK and would be candidates for targeted therapies. Moreover, one-third of at least one RTK overexspressing cases showed multiple RTKs expression. Our results may be useful for selecting the most suitable patients for each targeted therapy.

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Section: Discussionmentioning

confidence: 99%

Expression profiles of HER2, EGFR, MET and FGFR2 in a large cohort of patients with gastric adenocarcinoma

et al. 2014

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“…For example, MET amplification or activation is a mechanism of resistance to EGFR inhibition in both NSCLC and colorectal carcinomas (7,22). Conversely, in MET-addicted gastric carcinomas, activation of the ERBB receptors EGFR and ERBB3 maintains resistance to MET inhibition (23). There is a gap in knowledge of the relationship and interactions between MET and the ERBB receptor family in breast cancer.…”

Section: Introductionmentioning

confidence: 99%

“…ERBB2 þ breast cancers (26,27), and have been shown to play a role in trastuzumab resistance (28,29). In addition, EGFR and ERBB3 can promote the resistance of METaddicted gastric carcinomas to MET inhibitors (23). Therefore, EGFR and ERBB3 are suspects in driving the resistance to ERBB2 or MET knockdown.…”

Section: Met and Erbb2 Compensate For Each Other During Targeted Knocmentioning

confidence: 99%

MET and ERBB2 Are Coexpressed in ERBB2+ Breast Cancer and Contribute to Innate Resistance

Paulson

Linklater

Berghuis

et al. 2013

Molecular Cancer Research

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Breast cancer displays significant intratumoral heterogeneity, which has been shown to have a substantial impact on both innate and acquired resistance to tyrosine kinase inhibitors. The heterogeneous expression of multiple receptor tyrosine kinases (RTK) in cancers supports tumor signaling robustness and plays a significant role in resistance to targeted inhibition. Recent studies have revealed interactions between the MET receptor and the ERBB receptor family in the therapeutic resistance of several cancers. In this study, the relationship between MET expression/activity and the expression/activity of the ERBB receptor family in human breast cancer was interrogated. Importantly, a significant percentage of ERBB2 þ tumors coexpressing MET and ERBB2 were observed and displayed significant heterogeneity with subpopulations of cells that are MET À / ERBB2 þ , MET þ /ERBB2 À , and MET þ /ERBB2 þ . In a MET þ /ERBB2 þ breast cancer cell line, MET depletion resulted in increased ERBB2 activation, and conversely, ERBB2 depletion resulted in increased MET activation. Neither EGFR nor ERBB3 compensated for MET or ERBB2 knockdown. The loss of either MET or ERBB2 led to a decrease in PI3K/AKT signaling and increased dependency on MAPK. These data show that a subset of ERBB2 þ breast cancers express MET and contain MET þ /ERBB2 þ subpopulations. Moreover, analysis of RTK activation during ERBB2 knockdown indicated that MET signaling is a compensatory pathway of resistance.

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“…Recent clinical trials have been designed with molecular alterations of cMET, EGFR/RAS/RAF as biomarkers (56,61,84). Future clinical trials may also assess molecular derangements such as cMET mutation, K-ras amplification, EGFR and HER2 status as predictive markers (14,15,83,84,86).…”

Section: Resultsmentioning

confidence: 99%

“…An in vitro and in vivo study indicated that gastric cancer tumors bearing constitutive activation of HER family members responded poorly to MET inhibition (83). cMET activation may mediate resistance to EGFR and HER2 in gastric cancer (14,15).…”

Section: Resistance To Cmet Inhibitorsmentioning

confidence: 99%

cMET as a potential therapeutic target in gastric cancer (Review)

Lü

2013

International Journal of Molecular Medicine

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Abstract. Gastric cancer is one of the most common malignancies worldwide. Despite improvements in surgery and chemotherapy, the outcomes in patients with advanced gastric cancer remain poor. cMET is a member of the receptor tyrosine kinase family, and plays a key role in tumor survival, growth, angiogenesis and metastasis. cMET overexpression and/or gene amplification occurs in a significant proportion of gastric cancers. cMET is associated with a high tumor stage and poor prognosis. Several cMET inhibitors have been investigated in clinical trials, and the initial results are encouraging. It has become increasingly apparent that cMET is a promising therapeutic target in gastric cancer. In this review, we summarize the development of cMET inhibitors in the preclinical and clinical environment. In addition, we discuss the challenges of cMETtargeted therapy in gastric cancer and explore possible solutions.

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Activation of HER family members in gastric carcinoma cells mediates resistance to MET inhibition

Cited by 93 publications

References 46 publications

Expression profiles of HER2, EGFR, MET and FGFR2 in a large cohort of patients with gastric adenocarcinoma

Expression profiles of HER2, EGFR, MET and FGFR2 in a large cohort of patients with gastric adenocarcinoma

MET and ERBB2 Are Coexpressed in ERBB2+ Breast Cancer and Contribute to Innate Resistance

cMET as a potential therapeutic target in gastric cancer (Review)

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