Mesenchymal-epithelial Transition Factor Inhibitor Research Articles

Discovery of Pyrazolopyrazines as Selective, Potent, and Mutant-Active MET Inhibitors with Intracranial Efficacy.

Mesenchymal-epithelial transition factor (MET) is a receptor tyrosine kinase that serves a critical function in numerous developmental, morphogenic, and proliferative signaling pathways. If dysregulated, MET has been shown to be involved in the development and survival of several cancers, including non-small cell lung cancer (NSCLC), renal cancer, and other epithelial tumors. Currently, the clinical efficacy of FDA approved MET inhibitors is limited by on-target acquired resistance, dose-limiting toxicities, and less than optimal efficacy against brain metastasis. Therefore, there is still an unmet medical need for the development of MET inhibitors to address these issues. Herein we report the application of structure-based design for the discovery and development of a novel class of brain-penetrant MET inhibitors with enhanced activity against clinically relevant mutations and improved selectivity. Compound 13 with a MET D1228N cell line IC50 value of 23 nM showed good efficacy in an intracranial tumor model and increased the median overall survival of the animals to 100% when dosed orally at 100 mg/kg daily for 21 days.

Atomic Force Microscopy Lifetime Analysis: An Intuitive Method for Evaluating Receptor Tyrosine Kinase Dimer-Targeting Inhibitors.

Overexpression of receptor tyrosine kinases (RTKs) or binding to ligands can lead to the formation of specific unliganded and liganded RTK dimers, and these two RTK dimers are potential targets for preventing tumor metastasis. Traditional RTK dimer inhibitor analysis was mostly based on end point assays, which required cumbersome cell handling and behavior monitoring. There are still challenges in developing intuitive process-based analytical methods to study RTK dimer inhibitors, especially those used to visually distinguish between unliganded and liganded RTK dimer inhibitors. Herein, taking the mesenchymal-epithelial transition factor (MET) receptor, an intuitive method for evaluating MET inhibitors has been developed based on atomic force microscopy (AFM) lifetime analysis. The time interval between the start of the force and the bond break point was regarded as the bond lifetime, which could reflect the stability of the MET dimer. The results showed that there was a significant difference in the lifetime (τ) of unliganded MET dimers (τ1 = 207.87 ± 4.69 ms) and liganded MET dimers (τ2 = 330.58 ± 15.60 ms) induced by the hepatocyte growth factor, and aptamer SL1 could decrease τ1 and τ2, suggesting that SL1 could inhibit both unliganded and liganded MET dimers. However, heparin only decreased τ2, suggesting that it could inhibit only the liganded MET dimer. AFM-based lifetime analysis methods could monitor RTK dimer status rather than provide overall average results, allowing for intuitive process-based analysis and evaluation of RTK dimers and related inhibitors at the single-molecule level. This study provides a novel complementary strategy for simple and intuitive RTK inhibitor research.

Hepatocyte growth factor promotes retinal pigment epithelium cell activity through MET/AKT signaling pathway.

To explore the effects of hepatocyte growth factor (HGF) on retinal pigment epithelium (RPE) cell behaviors. The human adult retinal pigment epithelial cell line-19 (ARPE-19) were treated by HGF or mesenchymal-epithelial transition factor (MET) inhibitor SU11274 in vitro. Cell viability was detected by a Cell Counting Kit-8 assay. Cell proliferation and motility was detected by a bromodeoxyuridine incorporation assay and a wound healing assay, respectively. The expression levels of MET, phosphorylated MET, protein kinase B (AKT), and phosphorylated AKT proteins were determined by Western blot assay. The MET and phosphorylated MET proteins were also determined by immunofluorescence assay. HGF increased ARPE-19 cells' viability, proliferation and migration, and induced an increase of phosphorylated MET and phosphorylated AKT proteins. SU11274 significantly reduced cell viability, proliferation, and migration and decreased the expression of MET and AKT proteins. SU11274 suppressed HGF-induced increase of viability, proliferation, and migration in ARPE-19 cells. Additionally, SU11274 also blocked HGF-induced phosphorylation of MET and AKT proteins. HGF enhances cellular viability, proliferation, and migration in RPE cells through the MET/AKT signaling pathway, whereas this enhancement is suppressed by the MET inhibitor SU11274. HGF-induced MET/AKT signaling might be a vital contributor of RPE cells survival.

Remarkable response to capmatinib in a patient with intrahepatic cholangiocarcinoma harboring TFG-MET fusion.

Dysregulation of mesenchymal-epithelial transition factor (MET) gene due to amplification, mutation, and fusion has been reported in various types of human cancers. Recently, the efficacy of small-molecule tyrosine kinase inhibitors (TKIs) targeting MET has been demonstrated in a wide range of MET-dysregulated tumors. The majority of biliary tract cancers including intrahepatic cholangiocarcinoma (iCCA) are diagnosed at an advanced stage, and the utility of conventional chemotherapy is limited. Here, we present a case of metastatic iCCA harboring TFG-MET gene fusion, which demonstrated a remarkable response to treatment with capmatinib, a selective MET inhibitor. The patient was a 46-year-old man diagnosed with iCCA with hepatic, intraabdominal lymph nodes, and peritoneal metastases. Comprehensive genomic profiling (CGP) revealed TFG-MET gene fusion in his tumor. After becoming refractory to standard chemotherapy, he received capmatinib, which resulted in a marked shrinkage of the liver masses and lymph node metastases, as well as a drastic decrease in serum CA19-9 level. Our case reinforces the importance of CGP in exploring targeted therapy and supports the potential role of capmatinib in the treatment of tumors harboring MET fusions.

A Systematic Review of Mesenchymal Epithelial Transition Factor (MET) and Its Impact in the Development and Treatment of Non-Small-Cell Lung Cancer.

Lung cancer represents the leading cause of annual cancer-related deaths worldwide, accounting for 12.9%. The available treatment options for patients who experience disease progression remain limited. Targeted therapeutic approaches are promising but further understanding of the role of genetic alterations in tumorigenesis is imperative. The MET gene has garnered great interest in this regard. The aim of this systematic review was to analyze the findings from multiple studies to provide a comprehensive and unbiased summary of the evidence. A systematic search was conducted in the reputable scientific databases Embase and PubMed, leading to the inclusion of twenty-two articles, following the PRISMA guidelines, elucidating the biological role of MET in lung cancer and targeted therapies. The systematic review was registered in PROSPERO with registration ID: CRD42023437714. MET mutations were detected in 7.6-11.0% of cases while MET gene amplification was observed in 3.9-22.0%. Six studies showed favorable treatment outcomes utilizing MET inhibitors compared to standard treatment or placebo, with increases in PFS and OS ranging from 0.9 to 12.4 and 7.2 to 24.2 months, respectively, and one study reporting an increase in ORR by 17.3%. Furthermore, patients with a higher mutational burden may derive greater benefit from treatment with MET tyrosine kinase inhibitors (TKIs) than those with a lower mutational burden. Conversely, two studies reported no beneficial effect from adjunctive treatment with a MET targeted therapy. Given these findings, there is an urgent need to identify effective therapeutic strategies specifically targeting the MET gene in lung cancer patients.

Assessment of the potential of the MET inhibitor tepotinib to affect the pharmacokinetics of CYP3A4 and P-gp substrates

SummaryTepotinib is a highly selective, potent, mesenchymal-epithelial transition factor (MET) inhibitor, approved for the treatment of non-small cell lung cancer harboring MET exon 14 skipping alterations. The aims of this work were to investigate the potential for drug-drug interactions via cytochrome P450 (CYP) 3A4/5 or P-glycoprotein (P-gp) inhibition. In vitro studies were conducted in human liver microsomes, human hepatocyte cultures and Caco-2 cell monolayers to investigate whether tepotinib or its major metabolite (MSC2571109A) inhibited or induced CYP3A4/5 or inhibited P-gp. Two clinical studies were conducted to investigate the effect of multiple dose tepotinib (500 mg once daily orally) on the single dose pharmacokinetics of a sensitive CYP3A4 substrate (midazolam 7.5 mg orally) and a P-gp substrate (dabigatran etexilate 75 mg orally) in healthy participants. Tepotinib and MSC2571109A showed little evidence of direct or time-dependent CYP3A4/5 inhibition (IC50 > 15 μM) in vitro, although MSC2571109A did show mechanism-based CYP3A4/5 inhibition. Tepotinib did not induce CYP3A4/5 activity in vitro, although both tepotinib and MSC2571109A increased CYP3A4 mRNA. In clinical studies, tepotinib had no effect on the pharmacokinetics of midazolam or its metabolite 1’-hydroxymidazolam. Tepotinib increased dabigatran maximum concentration and area under the curve extrapolated to infinity by 38% and 51%, respectively. These changes were not considered to be clinically relevant. Tepotinib was considered safe and well tolerated in both studies. The potential of tepotinib to cause clinically relevant DDI with CYP3A4- or P-gp-dependent drugs at the clinical dose is considered low. Study 1 (midazolam): NCT03628339 (registered 14 August 2018). Study 2 (dabigatran): NCT03492437 (registered 10 April 2018).

Expert Consensus on Targeted Therapy of NSCLC with MET Exon 14 Skipping Mutation

The mesenchymal-epithelial transition factor (MET) exon 14 skipping mutation is mainly caused by the loss of c-Cbl tyrosine binding site. This mutation could result in a decrease in the degradation rate of proteasome-mediated MET proteins, trigger continuous activation of downstream pathways, and ultimately lead to tumorigenesis. The incidence of MET exon 14 skipping mutation in patients with non-small cell lung cancer (NSCLC) is 0.9% to 4.0%. Patients with advanced NSCLC are recommended to test MET exon 14 skipping mutations who may benefit from MET inhibitors-targeted therapy. MET inhibitors have a high objective response rate and good safety profiles, which could prolong the survival of NSCLC patients with MET exon 14 skipping mutations. The Lung Cancer Specialty Committee of Chinese Elderly Health Care Association organized multidisciplinary experts to give suggestions on the important issues of clinical aspects for targeted therapy of MET exon 14 skipping mutation in NSCLC according to the clinical practice experiences and evidences based medicine. "Expert Consensus on Targeted Therapy of NSCLC with MET Exon 14 Skipping Mutation" is proposed, aiming to provide standardized guidances for the clinical practice of Chinese physicians. .

The Preclinical Pharmacology of Tepotinib-A Highly Selective MET Inhibitor with Activity in Tumors Harboring MET Alterations.

The mesenchymal-epithelial transition factor (MET) proto-oncogene encodes the MET receptor tyrosine kinase. MET aberrations drive tumorigenesis in several cancer types through a variety of molecular mechanisms, including MET mutations, gene amplification, rearrangement, and overexpression. Therefore, MET is a therapeutic target and the selective type Ib MET inhibitor, tepotinib, was designed to potently inhibit MET kinase activity. In vitro, tepotinib inhibits MET in a concentration-dependent manner irrespective of the mode of MET activation, and in vivo, tepotinib exhibits marked, dose-dependent antitumor activity in MET-dependent tumor models of various cancer indications. Tepotinib penetrates the blood-brain barrier and demonstrates strong antitumor activity in subcutaneous and orthotopic brain metastasis models, in-line with clinical activity observed in patients. MET amplification is an established mechanism of resistance to EGFR tyrosine kinase inhibitors (TKI), and preclinical studies show that tepotinib in combination with EGFR TKIs can overcome this resistance. Tepotinib is currently approved for the treatment of adult patients with advanced or metastatic non-small cell lung cancer harboring MET exon 14 skipping alterations. This review focuses on the pharmacology of tepotinib in preclinical cancer models harboring MET alterations and demonstrates that strong adherence to the principles of the Pharmacological Audit Trail may result in a successful discovery and development of a precision medicine.

Single low-dose INC280-loaded theranostic nanoparticles achieve multirooted delivery for MET-targeted primary and liver metastatic NSCLC

BackgroundNon-small cell lung cancer (NSCLC) patients with primary tumors and liver metastases have substantially reduced survival. Since mesenchymal-epithelial transition factor (MET) plays a significant role in the molecular mechanisms of advanced NSCLC, small molecule MET inhibitor capmatinib (INC280) hold promise for clinically NSCLC treatment. However, the major obstacles of MET-targeted therapy are poor drug solubility and off-tumor effects, even oral high-dosing regimens cannot significantly increase the therapeutic drug concentration in primary and metastatic NSCLC.MethodsWe developed a multirooted delivery system INC280-PFCE nanoparticles (NPs) by loading INC280 into perfluoro-15-crown-5-ether for improving MET-targeted therapy. Biodistribution and anti-MET/antimetastatic effects of NPs were validated in orthotopic NSCLC and NSCLC liver metastasis models in a single low-dose. The efficacy of INC280-PFCE NPs was also explored in human NSCLC specimens.ResultsINC280-PFCE NPs exhibited excellent antitumor ability in vitro. In orthotopic NSCLC models, sustained release and prolonged retention behaviors of INC280-PFCE NPs within tumors could be visualized in real-time by 19F magnetic resonance imaging (19F-MRI), and single pulmonary administration of NPs showed more significant tumor growth inhibition than oral administration of free INC280 at a tenfold higher dose. Furthermore, a single low-dose INC280-PFCE NPs administered intravenously suppressed widespread dissemination of liver metastasis without systemic toxicity. Finally, we verified the clinical translation potential of INC280-PFCE NPs in human NSCLC specimens.ConclusionsThese results demonstrated high anti-MET/antimetastatic efficacies, real-time MRI visualization and high biocompatibility of NPs after a single low-dose.

Loss of Tpl2 activates compensatory signaling and resistance to EGFR/MET dual inhibition in v-RAS transduced keratinocytes.

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer in the United States, affecting one million people per year. Patients with aggressive disease have limited treatment options and high mortality, highlighting the need to identify new biomarkers linked to poor clinical outcome. HRAS mutations are found in skin papillomas and cSCCs and increase in frequency when MAP3K family members are inhibited, suggesting a link between blockade of mitogen-activated protein kinase (MAPK) signaling and initiation of RAS-primed cells. Tpl2, a MAP3K gene, can serve as a tumor suppressor gene in cSCC. We have previously shown that upon Tpl2 ablation, mice have heightened sensitivity to aberrant RAS signaling. Tpl2-/- mice display significantly higher numbers of papillomas and cSCCs in two-stage chemical carcinogenesis studies and increased tumorigenicity of keratinocytes expressing oncogenic v-rasHa in nude mouse skin grafts. In part, this is mediated through increased mesenchymal-epithelial transition factor (MET) receptor activity. Epidermal Growth Factor Receptor (EGFR) is reported to be an essential factor for MET-driven carcinogenesis and MET activation may confer resistance to EGFR therapies, suggesting that the concurrent use of both an EGFR inhibitor and a MET inhibitor may show promise in advanced cSCCs. In this study we assessed whether normal or Ras-transformed Tpl2-/- keratinocytes have aberrant EGFR signaling and whether concomitant treatment with EGFR/MET tyrosine kinase inhibitors was more effective than single agents in reducing growth and angiogenic potential of Ras-transformed keratinocytes. Tpl2-/- keratinocytes exhibited increased HER-2 and STAT-3 under basal conditions and elevated p-MET and p-EGFR when transduced with oncogenic RAS. Inhibition of MET by Capmatinib increased p-EGFR in Tpl2-/- keratinocytes and papillomas, and inhibition of EGFR by Gefitinib increased HER2 and HER3 signaling in both genotypes. Treatment of keratinocytes with EGFR and MET inhibitors, in combination, significantly enhanced endothelial tube formation, MMP-9 activity and activation of other RTKs, with more pronounced effects when Tpl2 was ablated. These data indicate that Tpl2 cross-talks with both EGFR and MET signaling pathways. Upon inhibition of EGFR/MET signaling, a myriad of escape mechanisms exists in keratinocytes to overcome targeted drug effects.

Mesenchymal-epithelial Transition Factor Regulates Monocyte Function during Mycobacterial Infection via Indoleamine 2,3-dioxygenase.

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), causes an estimated 1.6 million human deaths annually, but the pathogenesis of TB remains unclear. Immunity plays a critical role in the onset and outcome of TB. This study aimed to uncover the roles of innate and adaptive immunity in TB. The gene expression profiles generated by RNA sequencing from human peripheral blood mononuclear cells (PBMCs) stimulated with or without Mtb strain H37Rv antigens were analyzed. A total of 973 differentially expressed mRNAs were identified. The differentially expressed genes were enriched in innate immunity signaling functions. The mesenchymal-epithelial transition factor (MET) gene was significantly upregulated in CD14+ monocytes. A MET inhibitor improved the uptake of the BCG strain by monocytes and macrophages as well as inhibited the expression of indoleamine 2,3-dioxygenase (IDO). The expression of IDO was increased in PBMCs stimulated with Mtb antigens, and the IDO inhibitor promoted the expression of CD40, CD83, and CD86. Our results might provide clues regarding the immunomodulatory mechanisms used by Mtb to evade the host defense system.

Discovery of amivantamab (JNJ-61186372), a bispecific antibody targeting EGFR and MET

A bispecific antibody (BsAb) targeting the epidermal growth factor receptor (EGFR) and mesenchymal–epithelial transition factor (MET) pathways represents a novel approach to overcome resistance to targeted therapies in patients with non–small cell lung cancer. In this study, we sequentially screened a panel of BsAbs in a combinatorial approach to select the optimal bispecific molecule. The BsAbs were derived from different EGFR and MET parental monoclonal antibodies. Initially, molecules were screened for EGFR and MET binding on tumor cell lines and lack of agonistic activity toward MET. Hits were identified and further screened based on their potential to induce untoward cell proliferation and cross-phosphorylation of EGFR by MET via receptor colocalization in the absence of ligand. After the final step, we selected the EGFR and MET arms for the lead BsAb and added low fucose Fc engineering to generate amivantamab (JNJ-61186372). The crystal structure of the anti-MET Fab of amivantamab bound to MET was solved, and the interaction between the two molecules in atomic details was elucidated. Amivantamab antagonized the hepatocyte growth factor (HGF)-induced signaling by binding to MET Sema domain and thereby blocking HGF β-chain—Sema engagement. The amivantamab EGFR epitope was mapped to EGFR domain III and residues K443, K465, I467, and S468. Furthermore, amivantamab showed superior antitumor activity over small molecule EGFR and MET inhibitors in the HCC827-HGF in vivo model. Based on its unique mode of action, amivantamab may provide benefit to patients with malignancies associated with aberrant EGFR and MET signaling.

Progress on Mechanism of MET Gene Mutation and Targeted Drugs in Non-small Cell Lung Cancer

间质-上皮细胞转化因子（mesenchymal-epithelial transition factor, MET）基因是非小细胞肺癌（non-small cell lung cancer, NSCLC）的一种重要肿瘤驱动基因，针对MET 14外显子的跳跃突变的靶向治疗药物给患者带来新的希望。目前已经上市或者即将上市的MET抑制剂包括：克唑替尼、卡博替尼、沃利替尼和Tepotinib等。MET抑制剂的客观缓解率较高，并且安全性良好。但是，MET抑制剂的耐药不可避免，因此需要重视对于耐药机制的研究。肝细胞生长因子（hepatocyte growth factor, HGF）/MET信号通路抑制剂与其他药物的联合应用，对于抑制和逆转耐药可能发挥重要作用。

High-level gain of mesenchymal-epithelial transition factor (MET) copy number using next-generation sequencing as a predictive biomarker for MET inhibitor efficacy.

BackgroundIn clinical oncology, targeted next-generation sequencing (NGS) has become an integral part of the routine molecular diagnostics repertoire. However, a consensus is yet to be agreed on the optimal mesenchymal-epithelial transition factor (MET) copy number (CN) cut-off value based on NGS data that could predict the MET-amplified non-small cell lung cancer (NSCLC) patients who could benefit from MET tyrosine kinase inhibitor (TKI) therapy. In this study, we aimed to identify the criteria to define MET amplification derived from NGS data.MethodsSequencing data from matched plasma and tissue samples from 40 MET-amplified NSCLC patients were used to derive a normalization method, referred to as adjusted copy number (adCN). Clinical outcomes from an additional 18 MET TKI-treated NSCLC patients with solely MET-amplified cancers were analyzed to validate the adCN cut-offs.ResultsAdCN, calculated as the absolute CN generated from NGS relative to the maximum mutant allele fraction (maxMAF) per sample, was demonstrated to have a high correlation with MET CN in tissue and plasma samples (R2=0.73). Using a cut-off value of 5.5 and 13, tertile stratification of adCN was able to distinguish patients with high-level MET amplification. The MET TKI-treated patients with adCN >13, categorized as high-level amplification, had significantly longer progression-free survival (PFS) than those with adCN <13 (P=0.009), suggesting that adCN positively correlated with the response to MET TKI.ConclusionsWe derived a normalization method that could reflect the relative CN and distinguish MET-amplified NSCLC patients with high-level gene amplification who were sensitive to crizotinib, suggesting adCN could potentially serve as a predictive biomarker for MET TKI response.

Circular RNA circBFAR promotes the progression of pancreatic ductal adenocarcinoma via the miR-34b-5p/MET/Akt axis

BackgroundAccumulating evidence suggests that circular RNAs (circRNAs) are important participants in cancer progression. However, the biological processes and underlying mechanisms of circRNAs in pancreatic ductal adenocarcinoma (PDAC) are unclear.MethodCircRNAs were verified by Sanger sequencing. Colony formation, 5-Ethynyl-2′-deoxyuridine (EdU), and Transwell assays were performed to investigate the effect of circBFAR on the proliferation, invasion, and migration of PDAC cells in vitro. RNA pull-down assays were conducted to verify the binding of circBFAR with microRNA miR-34b-5p.ResultsIn the present study, we identified a novel circRNA (termed as circBFAR, hsa_circ_0009065) that was upregulated in a 208-case cohort of patients with PDAC. The ectopic expression of circBFAR correlated positively with the tumor-node-metastasis (TNM) stage and was related to poorer prognosis of patients with PDAC. Moreover, circBFAR knockdown dramatically inhibited the proliferation and motility of PDAC cells in vitro and their tumor-promoting and metastasis properties in in vivo models. Mechanistically, circBFAR upregulated mesenchymal-epithelial transition factor (MET) expression via sponging miR-34b-5p. Additionally, circBFAR overexpression increased the expression of MET and activated downstream phosphorylation of Akt (Ser 473) and further activated the MET/PI3K/Akt signaling pathway, which ultimately promoted the progression of PDAC cells. Importantly, application of MET inhibitors could significantly attenuate circBFAR-mediated tumorigenesis in vivo.ConclusionsOur findings showed that circBFAR plays an important role in the proliferation and metastasis of PDAC, which might be explored as a potential prognostic marker and therapeutic target for PDAC.

MET Oncogene in Non-Small Cell Lung Cancer: Mechanism of MET Dysregulation and Agents Targeting the HGF/c-Met Axis.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide and has a poor prognosis. Current treatments for advanced NSCLC included traditional chemotherapy, radiotherapy, targeted therapy, and immunotherapy. The efficacy of targeted therapy relies on oncogene addiction. Mesenchymal-epithelial transition factor (MET) gene can encode unconventional receptor tyrosine kinases with pleiotropic functions, when signals are abnormally activated, it can initiate and maintain tumor transformation, promote cell proliferation, survival, tumor invasion and angiogenesis. Thus, it is a promising therapeutic target. Previous studies have shown that elevated levels of HGF and/or overexpression of c-Met are associated with poor prognosis in lung cancer. In preclinical and clinical trials, c-MET inhibitors have shown some antitumor activity in NSCLC. Although the efficacy results of MET inhibitors in Phase III clinical trials are disappointing, given the molecular heterogeneity of NSCLC, only subgroups of patients with MET gene alterations may benefit from c-MET inhibitors. The challenge for the future is to screen out the potential beneficiaries. To solve this problem, there is need for large data analysis for the detection methods and treatment effects, to establish standards that meet the MET activation status, and determine reliable thresholds to achieve effective patient stratification and clinical decision making. This article summarized the structure of the hepatocyte growth factor (HGF)/c-Met axis, the different mechanisms of MET addiction, as well as MET amplification as acquired resistance mechanism to epidermal growth factor receptor-tyrosine kinase inhibitors, the latest advances of MET inhibitors, and immuotherapy in the treatment of NSCLC with MET alterations.

Co-expression of EGFR and MET has a synergistic effect on the prognosis of patients with oral squamous cell carcinoma.

This study aimed to elucidate the correlation between gene amplification, protein expression of receptor tyrosine kinase, and prognosis of patients with oral squamous cell carcinoma (OSCC) using immunohistochemistry (IHC) and next-generation sequencing data. We evaluated data pertaining to 208 patients with OSCC using IHC for epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET). High expressions of EGFR and MET were detected in 60 and 41 patients, respectively. We evaluated the association of clinicopathological variables with high expressions of EGFR and/or MET. Distant metastasis was found in 9 of 41 patients (22.0%) and 6 of 15 patients (40.0%) with high expression of MET and high co-expressions of EGFR and MET, respectively; statistically significant differences were detected in both high expression of MET (P=.003) and high co-expressions of EGFR and MET (P=3.41×10-5 ). The cumulative 5-year survival rate of patients with high and low expressions of EGFR or MET was approximately 65% and 85%, respectively. Conversely, among cases with high expressions of EGFR or MET, there was no additional decrease in the survival rate of patients harboring TP53 mutations. Moreover, the survival rate of patients with high co-expression of both EGFR and MET was very poor (22.0%) (P<1.0×10-9 ). Our findings suggest that evaluation of protein expressions of EGFR and MET may facilitate prognostic assessment of patients with OSCC; in addition, patients with OSCC should be screened for enrollment in clinical trials of combination therapy with EGFR and MET inhibitors.

Clonal MET Amplification as a Determinant of Tyrosine Kinase Inhibitor Resistance in Epidermal Growth Factor Receptor–Mutant Non–Small-Cell Lung Cancer

Mesenchymal epithelial transition factor ( MET) activation has been implicated as an oncogenic driver in epidermal growth factor receptor ( EGFR)-mutant non-small-cell lung cancer (NSCLC) and can mediate primary and secondary resistance to EGFR tyrosine kinase inhibitors (TKI). High copy number thresholds have been suggested to enrich for response to MET inhibitors. We examined the clinical relevance of MET copy number gain (CNG) in the setting of treatment-naive metastatic EGFR-mutant-positive NSCLC. MET fluorescence in situ hybridization was performed in 200 consecutive patients identified as metastatic treatment-naïve EGFR-mutant-positive. We defined MET-high as CNG greater than or equal to 5, with an additional criterion of MET/centromeric portion of chromosome 7 ratiο greater than or equal to 2 for amplification. Time-to-treatment failure (TTF) to EGFR TKI in patients identified as MET-high and -low was estimated by Kaplan-Meier method and compared using log-rank test. Multiregion single-nucleotide polymorphism array analysis was performed on 13 early-stage resected EGFR-mutant-positive NSCLC across 59 sectors to investigate intratumoral heterogeneity of MET CNG. Fifty-two (26%) of 200 patients in the metastatic cohort were MET-high at diagnosis; 46 (23%) had polysomy and six (3%) had amplification. Median TTF was 12.2 months (95% CI, 5.7 to 22.6 months) versus 13.1 months (95% CI, 10.6 to 15.0 months) for MET-high and -low, respectively ( P = .566), with no significant difference in response rate regardless of copy number thresholds. Loss of MET was observed in three of six patients identified as MET-high who underwent postprogression biopsies, which is consistent with marked intratumoral heterogeneity in MET CNG observed in early-stage tumors. Suboptimal response (TTF, 1.0 to 6.4 months) to EGFR TKI was observed in patients with coexisting MET amplification (five [3.2%] of 154). Although up to 26% of TKI-naïve EGFR-mutant-positive NSCLC harbor high MET CNG by fluorescence in situ hybridization, this did not significantly affect response to TKI, except in patients identified as MET-amplified. Our data underscore the limitations of adopting arbitrary copy number thresholds and the need for cross-assay validation to define therapeutically tractable MET pathway dysregulation in EGFR-mutant-positive NSCLC.

Two are better than one on progression through MET mechanism for EGFR+ NSCLC patients

Recent years have borne witness to the development of numerous acquired resistances to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) treatment for patients with EGFR-mutated non-small cell lung cancer (NSCLC). Mechanism of resistant includes EGFR T790M, MET gene amplification (1,2), transformation to small cell lung cancer and others. Approximately 5 to 26 percent of these acquired modifications occur due to dysregulation of the mesenchymal-epithelial transition factor (MET) either by amplification or overexpression patterns. Previous studies have failed to show efficacy of adding MET inhibitors to EGFR-TKI therapies upon progression (3).

Peptide-Functionalized Nanoinhibitor Restrains Brain Tumor Growth by Abrogating Mesenchymal-Epithelial Transition Factor (MET) Signaling.

Malignant gliomas are themost common primary brain tumors and are associated with aggressive growth, high morbidity, and mortality. Aberrant mesenchymal-epithelial transition factor (MET) activation occurs in approximately 30% of glioma patients and correlates with poor prognosis, elevated invasion, and increased drug resistance. Therefore, MET has emerged as an attractive target for glioma therapy. In this study, we developed a novel nanoinhibitor by conjugating MET-targeting cMBP peptides on the G4 dendrimer. Compared to the binding affinity of the free peptide ( KD = 3.96 × 10-7 M), the binding affinity of the nanoinhibitor to MET increased 3 orders of magnitude to 1.32 × 10-10 M. This nanoinhibitor efficiently reduced the proliferation and invasion of human glioblastoma U87MG cells in vitro by blocking MET signaling with remarkably attenuated levels of phosphorylated MET ( pMET) and its downstream signaling proteins, such as pAKT and pERK1/2. Although no obvious therapeutic effect was observed after treatment with free cBMP peptide, in vivo T2-weighted magnetic resonance imaging (MRI) showed a significant delay in tumor growth after intravenous injection of the nanoinhibitor. The medium survival in mouse models was extended by 59%, which is similar to the effects of PF-04217903, a small molecule MET inhibitor currently in clinical trials. Immunoblotting studies of tumor homogenate verified that the nanoinhibitor restrained glioma growth by blocking MET downstream signaling. pMET and its downstream proteins pAKT and pERK1/2, which are involved in the survival and invasion of cancer cells, decreased in the nanoinhibitor-treated group by 44.2%, 62.2%, and 32.3%, respectively, compared with those in the control group. In summary, we developed a peptide-functionalized MET nanoinhibitor that showed extremely high binding affinity to MET and effectively inhibited glioma growth by blocking MET downstream signaling. To the best of our knowledge, this is the first report of therapeutic inhibition of glioma growth by blocking MET signaling with a novel nanoinhibitor. Compared to antibodies and chemical inhibitors in clinical trials, the nanoinhibitor blocks MET signaling and provides a new approach for the treatment of glioma with the advantages of high efficiency, affordability, and, most importantly, potentially reduced drug resistance.