Mesenchymal-epithelial Transition Overexpression Research Articles

MET overexpression in EGFR L858R mutant treatment-naïve advanced lung adenocarcinoma correlated with poor prognosis: a real-world retrospective study.

Mesenchymal epithelial transition (MET) overexpression has been reported in approximately 50-60% of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancers. However, the prognostic significance of MET overexpression has not been established in advanced lung adenocarcinoma (ADC) patients with EGFR-sensitive mutations. A retrospective study was performed on a total of 406 treatment-naïve advanced ADC patients with EGFR mutation detection and MET expression information. EGFR mutations were detected by next-generation sequencing or amplification refractory mutation system-polymerase chain reaction. Immuno-histochemistry staining of MET expression was evaluated by H-score and overexpression was defined as an H-score ≥ 200. Overall survival (OS) and progression-free survival (PFS) were analyzed according to MET expression. Among the 406 patients, 208 patients had EGFR mutations, including 102 exon 19_del mutations, 94 L858R mutations and 12 other types of mutations. Of 110 patients with concomitant EGFR mutations and MET overexpression, 61 (59.8%) patients had 19_del mutations, 44 (46.8%) patients had L858R mutations and five (41.7%) patients had others. Patients with MET overexpression had a markedly shorter PFS and OS than patients with MET H-score < 200 in the EGFR L858R mutation subgroup (median PFS: 12 versus 26months, p = 0.001; median OS: 24 versus 32months, p = 0.038), whereas no significant difference was observed in 19_del mutation subgroup. Multivariate Cox analysis showed that MET overexpression was an independent poor prognostic factor for PFS and OS in patients with the L858R mutations (HR = 3.064, 95% CI 1.705-5.507, p < 0.001; HR = 2.043, 95% CI 1.000-4.172; p = 0.049), rather than 19_del. MET overexpression is a poor prognostic factor for advanced ADC patients with the EGFR L858R mutation.

Narrative review: mesenchymal-epithelial transition inhibitors-meeting their target.

Genetic alterations in mesenchymal-epithelial transition (MET) are commonly found in solid tumors, especially in non-small cell lung cancer (NSCLC). However, agents targeting MET have not progressed until recently. Advancements in our understanding of the role of various MET aberrations in carcinogenesis have allowed MET-directed therapy to find its way to clinic use. Of all MET alterations, MET exon 14 skipping (METex14 skip+ or MET∆14), stands out as a true oncogenic driver. Recently, MET tyrosine kinase inhibitors (TKI) targeting METex14 skipping were able to demonstrate significant improvement in clinical outcomes including response rate and progression free survival. Of these, capmatinib was granted accelerated approval by the FDA in May 2020 for patients with advanced NSCLC harboring METex14 skip alterations. Tepotinib, another TKI, has shown significant activity in a phase II trial and received breakthrough therapy designation from the FDA in September 2019. MET amplification (METAmp) and overexpression are usually a late phenomenon in tumorigenesis and aggravate malignant properties of transformed cells. Capmatinib and savolitinib have shown activity in patients with NSCLC with high levels of METAmp. Several other agents are being developed and under evaluation in clinical trials involving multiple tumor types. In addition to TKIs, MET overexpression is also an appealing target for development of antibody conjugated chemotherapy. Understanding the mechanisms of resistance to MET TKIs and alterations in anti-tumor immunity through MET inhibition are clinically relevant areas that need further exploration.

Effectiveness of crizotinib in a patient with mesenchymal-epithelial transition overexpression/fluorescence in situ hybridization-negative/next-generation sequencing-negative advanced lung adenocarcinoma: a case report

Crizotinib, an oral ATP-competitive tyrosine kinase inhibitor (TKI), has shown significant activity against advanced non-small cell lung cancer (NSCLC) tumors harboring mesenchymal-epithelial transition (MET) amplification or exon 14 mutation. Methods to detect MET alteration includes immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), next-generation sequencing (NGS) and reverse transcription polymerase chain reaction (RT-PCR). Despite multiple methods for detecting MET alteration, the response to crizotinib in advanced NSCLC patients according to the results of MET IHC staining is still unknown. This case showed effectiveness of crizotinib in a pretreated patient with advanced lung adenocarcinoma detected as MET overexpression/FISH-negative/NGS-negative. MET overexpression might be a biomarker for predicting efficacy of crizotinib.

Prognostic Significance of Mesenchymal–Epithelial Transition in Triple-Negative Breast Cancers

IntroductionThe prognostic value of the mesenchymal–epithelial transition (MET) in triple-negative breast cancers (TNBCs) remains controversial. A meta-analysis of the impact of MET in TNBCs was performed by searching published data. MethodsPubMed and Embase databases were searched for eligible literature. The principal outcome measures were hazard ratios (HRs) for recurrence-free survival or overall survival according to MET expression. Combined HRs were calculated using fixed- or random-effects models according to heterogeneity. ResultsSix studies involving 785 patients met our selection criteria. The meta-analysis results showed that MET overexpression was associated with a 1.29-fold increased risk of recurrence (combined HR 1.29; 95% confidence interval, 1.04-1.60; P = .020) in the TNBCs. Three studies provided the related overall survival data (488 cases). The results showed that MET overexpression was associated with a 1.38-fold increased risk of mortality (HR, 1.38; 95% confidence interval, 1.08-1.76; P = .009). ConclusionMET is an adverse prognostic marker for TNBCs. The results strengthen the rationale for targeted therapy of TNBCs using MET inhibitors in future clinical trials.

Abstract 2723: MET exon 14 skipping mutations in advanced non-small cell lung cancer (NSCLC) are not associated with MET amplification and overexpression

Abstract Background: Activating alterations of the mesenchymal epithelial transition (MET) oncogene in NSCLC are potentially actionable with targeted MET inhibitors. MET exon 14 skipping mutations have been described in 3% of patients (p) in NSCLC,.Fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC) are currently used for detecting MET amplification and overexpression, respectively, but are not useful to detect MET splicing variants. On the other hand, the reverse transcription-polymerase chain reaction (RT-PCR) technique has the potential to detect this actionable alteration. Methods: We designed and validated a custom set of 5´and 3´ primers to detect the MET exon 14 splicing variant by RT-PCR. RNA isolation from FFPE samples was performed with Roche High Pure FFPET RNA isolation kit and M-MLV Reverse Transcriptase enzyme was used in the RT-PCR. A panel of cell lines was initially employed to assess the performance of the technique. Subsequently, a total of 232 formalin-fixed paraffin-embedded (FFPE) samples from advanced NSCLC patients were analyzed. Of them, 15 were positive by RT-PCR (n=209) for the MET exon 14 variant. The bands corresponding to the splicing variant were submitted to Sanger sequencing. Results were compared with FISH (ZytoVision Dual Color probe Z-2087-200) and IHC (Ventana CONFIRM anti-Total c-MET (SP44)). Results: A total of 232 EGFR-wt advanced NSCLC p were analyzed by IHC and 42 (18.1%) were considered as positive (cut-off 3+≥ 50%). Regarding FISH, MET amplification was detected in 13 out of 58 p (22.4%) evaluable while the MET exon 14 skipping variant was detected in 15 (7.2%) out of 209 p . Unexpectedly, only three (21.4%) of the positive MET exon 14 skipping p by RT-PCR were positive for IHC. Finally, of the 15 MET exon 14 positive p, 5 were evaluable for FISH and none of them were positive for MET amplification. Conclusion: In our cohort of 232 EGFR-wt, advanced NSCLC p, the MET exon 14 skipping mutation had an incidence of 7.2% No correlation was found between the presence of the MET exon 14 variant by RT-PCR and MET overexpression or amplification. Detection of MET exon 14 alterations poses a challenge for diagnostic testing. Citation Format: Ana Gimenez-Capitan, Cristina Teixidó, Cristina Aguado, Sonia Rodríguez, Jordi Bertran-Alamillo, Josep Castellví, Zaira Yeste, Ana Pérez, Rafael Rosell, Miguel Angel Molina-Vila. MET exon 14 skipping mutations in advanced non-small cell lung cancer (NSCLC) are not associated with MET amplification and overexpression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2723. doi:10.1158/1538-7445.AM2017-2723

MET overexpression and gene amplification: prevalence, clinico-pathological characteristics and prognostic significance in a large cohort of patients with surgically resected NSCLC.

The prevalence of overexpression and amplification of the proto-oncogene mesenchymal epithelial transition (MET) in non-small cell lung cancer (NSCLC) varies greatly in the literature. Since MET is a potential treatment target, knowledge of its prevalence and prognostic importance is crucial. We investigated MET expression and gene status in 735 NSCLC cases using tissue microarrays. Prognostic significance as well as correlations with various clinico-pathological parameters were evaluated. The prevalence of MET overexpression was 17% and MET amplification was present in 2.4% of cases. MET overexpression was found more frequently in adenocarcinomas (and TTF1-positive tumors) and female patients and was also associated with expression of members of the epidermal growth factor receptor (EGFR) signaling cascade. MET amplified tumors tended to express MET more frequently and more intensively. MET expression or gene status did not prove to be relevant prognostic factors. MET may not be an unequivocal prognostic parameter; however, its expression is associated with certain clinico-pathological characteristics and with EGFR and downstream EGFR effectors. This could be an important point for future studies addressing targeted MET therapy and should be considered as a possible means of optimizing the benefit and minimizing undesirable effects.

MET deregulation in breast cancer.

Mesenchymal-epithelial transition (MET) is an oncogene encoding for a trans-membrane tyrosine kinase receptor activated by the hepatocyte growth factor (HGF). MET has a normal function in organ development during embryogenesis and in tissue homeostasis during adult life. Deregulation of HGF/MET signaling pathway is frequently observed in many cancer types, conferring invasive growth and tendency to progression. MET deregulation is due to gene amplification or increased copy number, gene mutation, receptor over-expression or ligand autocrine loops activation. These events lead to migration, invasion, proliferation, metastatic spread and neo-angiogenesis of cancer cells, suggesting that anti-HGF/MET agents may represent a potential antitumor strategy. In breast cancer (BC), preclinical and clinical data demonstrated the role of HGF/MET signalling pathway in carcinogenesis, disease progression and resistance features. For this review article, all published data on HGF/MET in BC were collected and analyzed. Several evidences underline that, in early BC, MET over-expression has an independent negative prognostic significance, regardless of method used for evaluation and BC subtypes. Available data suggest that MET is a relevant target particularly in basal-like (BL) and in triple negative BC. Moreover, preclinical and retrospective data support the critical role of MET deregulation in the development of resistance to target-agents, such as anti-HER2 strategies. MET is a promising new target in BC. Several anti-MET agents are under investigation and ongoing clinical trials will clarify its relevance in BC treatment.

Role of HGF-MET Signaling in Primary and Acquired Resistance to Targeted Therapies in Cancer.

The Hepatocyte growth factor (HGF)—mesenchymal-epithelial transition (MET) pathway is deregulated in several cancers and is associated with aggressive phenotype and worse prognosis. MET, a tyrosine kinase receptor activated by HGF, plays a physiological role in embryogenesis, promoting cell growth, survival and motility. HGF–MET aberrant activation in tumorigenesis acts through various mechanisms: paracrine/autocrine HGF production, MET overexpression, MET germ-line and sporadic mutations and cross-talk with other growth factor receptors. In addition, MET activation could represent a mechanism of escape from other targeted therapies, through receptor amplification or over-stimulation by the ligand, as demonstrated in non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) models with acquired resistance to epidermal growth factor receptor (EGFR) inhibitors and also in models of melanoma resistant to the BRAF inhibitor vemurafenib. As a consequence, a lot of molecules targeting MET signaling are under clinical investigation as single agent or in combination with other targeted drugs. Patient selection, based on MET expression on tumor samples (eventually, by re-biopsy of new metastatic sites), and pharmacokinetic/pharmacodynamic markers are needed. Authors review the latest data on the role of MET and the molecular mechanism underlying primary or acquired resistance to biological agents, focusing on NSCLC, CRC and melanoma.

Negative results of METLung study: an opportunity to better understand the role of MET pathway in advanced NSCLC.

The negative results of the global METLung phase III trial recently presented at American Society of Clinical Oncology (ASCO) were clearly unexpected (1). The trial assessed the impact on overall survival (OS) of adding onartuzumab, a monovalent monoclonal antibody against mesenchymal-epithelial transition (MET) factor receptor tyrosine kinase (RTK), to erlotinib in second or third-line therapy of advanced non-small cell lung cancer (NSCLC) patients with MET overexpression. There was a strong rationale behind this phase III trial: dysregulation of MET signaling in cancer is responsible for cell proliferation, cell cycle progression, cell dissociation, motility, spreading and invasion, overexpression of MET is linked to a worse prognosis for both early and late stages of NSCLC, and crosstalk with other RTKs including EGFR can lead to synergistic activation of downstream pathways. Moreover, amplification of MET seems to be involved in a significant proportion of patients with EGFR mutations developing acquired resistance to EGFR inhibitors.