c-Met Overexpression Research Articles

P2.07-01 Deep-Learning Based Prediction of c-MET Status from Digitized H&E-Stained Non-Small Cell Lung Cancer Tissue Samples

Genetic profiling of non-small cell lung cancer (NSCLC) tissue has identified alterations in a number of genes, including c-MET. Dysregulation of c-MET, a receptor tyrosine kinase mesenchymal epithelial transition factor, is associated with worse prognosis. Therapeutics targeting c-MET such as the antibody drug conjugate (ADC) Telisotuzimab vedotin (Teliso-V) may be of benefit. Currently, immunohistochemical staining of tissue is used to determine whether c-MET protein is overexpressed. Here we report development of a machine learning (ML)-powered method that identifies features of the tumor microenvironment (TME) as predictors of c-MET overexpression status (positive vs.

Application of C-MET Inhibitors in the Treatment of Non-small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) is a kind of refractory lung cancer. Under traditional cisplatin treatment, it is difficult for patients, especially the advanced cancer patients, to have a high cure rate and survival rate. Abnormal histological variants may lead to NSCLC. Mutations in C-MET may lead to abnormal downstream metabolism, which in turn triggers unrestricted cell growth and metastasis. Therefore, C-MET inhibitors can inhibitive the overexpression and activation of C-MET by blocking the gene pathway, in result in that the growth and the spread of cancer cell can be inhibitived. A variety of C-MET inhibitors such as crizotinib, cabonitinib, capmatinib, etc., have been found to have good therapeutic activity and considerable clinical data. This paper discussed the C-MET as a therapeutic target in NSCLC, and outline the applications in clinical and therapeutic effects of various C-MET inhibitors.

Paeoniflorin Inhibits EMT and Angiogenesis in Human Glioblastoma via K63-Linked C-Met Polyubiquitination-Dependent Autophagic Degradation.

Epithelial-to-mesenchymal transition (EMT) and angiogenesis have emerged as two pivotal events in cancer progression. Paeoniflorin has been widely studied in experimental models and clinical trials for cancer treatment because of its anti-cancer property. However, the underlying mechanisms of paeoniflorin in EMT and angiogenesis in glioblastoma was not fully elucidated. The present study aimed to investigate whether paeoniflorin inhibits EMT and angiogenesis, which involving c-Met suppression, while exploring the potential ways of c-Met degradation. In our study, we found that paeoniflorin inhibited EMT via downregulating c-Met signaling in glioblastoma cells. Furthermore, overexpressing c-Met in glioblastoma cells abolished the effects of paeoniflorin on EMT. Moreover, paeoniflorin showed anti-angiogenic effects by suppressing cell proliferation, migration, invasion and tube formation through downregulating c-Met in human umbilical vein endothelial cells (HUVECs). And c-Met overexpression in HUVECs offset the effects of paeoniflorin on angiogenesis. Additionally, paeoniflorin induced autophagy activation involving mTOR/P70S6K/S6 signaling and promoted c-Met autophagic degradation, a process dependent on K63-linked c-Met polyubiquitination. Finally, paeoniflorin suppressed mesenchymal makers (snail, vimentin, N-cadherin) and inhibited angiogenesis via the identical mechanism in an orthotopic xenograft mouse model. The in vitro and in vivo experiments showed that paeoniflorin treatment inhibited EMT, angiogenesis and activated autophagy. What’s more, for the first time, we identified c-Met may be a potential target of paeoniflorin and demonstrated paeoniflorin downregulated c-Met via K63-linked c-Met polyubiquitination-dependent autophagic degradation. Collectively, these findings indicated that paeoniflorin inhibits EMT and angiogenesis via K63-linked c-Met polyubiquitination-dependent autophagic degradation in human glioblastoma.

MACC1 Promotes the Progression and Is a Novel Biomarker for Predicting Immunotherapy Response in Colorectal Cancer.

Aims As one of the most prevalent malignant diseases in the world, the mechanisms of metastasis in colon cancer are poorly understood. The aim of this study was to investigate the role of the HGF/c-MET axis in the proliferation and metastasis in colon cancer. Methods The effect of MACC1 on cell proliferation and metastasis was analyzed through a series of in vitro experiments. The role of MACC1 in cancer cells was demonstrated by overexpression and silencing of MACC1 in gain or loss function experiments. To investigate the relationship between MACC1 and c-MET/HGF, we detected c-MET protein expression by disrupting with or overexpressing MACC1. The bioinformatics analysis was used to investigate the correlation between MACC1 and c-MET, and the c-MET expression after the interference of HGF with MACC1 was determined. Subsequently, the function of c-MET was verified in colon cancer cells by a series of experiments. The mouse tumor transplantation model experiment is most suitable in vivo. Results The results indicated that the overexpression of MACC1 could accelerate proliferation and facilitate metastasis in colon cancer cell lines. Furthermore, c-MET was determined to be the downstream regulator of MACC1. The addition of HGF could stimulate the expression of MACC1. With further exploration, we proved that c-MET is downstream of MACC1 in colon cancer and that overexpression of c-MET in colon cancer enhances cell proliferation and migration capability. At last, MACC1 expression level negatively correlates with the infiltration levels and several immune checkpoint biomarkers. High MACC1 expression has a lower response rate with ICIs in COAD. Conclusions We found that, under the regulation of the MACC1/HGF/c-MET axis, the proliferation and metastasis of colorectal cancer are increased by MACC1, which can be a novel biomarker for predicting ICIs response in colorectal cancer. Our findings provide a new idea for the targeted treatment of colorectal cancer.

MO31-2 Telisotuzumab vedotin monotherapy in patients with previously treated c-Met+ advanced non-small cell lung cancer

Telisotuzumab vedotin (Teliso-V) is an anti-c-Met antibody conjugated with a tubulin inhibitor, monomethylauristatin E. The c-Met receptor tyrosine kinase is the cell surface receptor for hepatocyte growth factor (HGF) encoded for by the MET proto-oncogene. c-Met overexpression occurs in various solid tumors, including non-small cell lung cancer (NSCLC), and the aberrant activation of the c-Met/HGF axis contributes to tumor progression, angiogenesis, invasive growth, metastasis, and resistance to therapies.

Abstract 1123: c-Met downregulation contributes to Metformin-induced inhibition of MDA-MB-468 triple negative breast cancer cells

Abstract Triple negative breast cancer (TNBC) is the breast cancer subtype that is most refractory to treatment. Thus, identification of novel molecular targets and drug treatments are needed to improve prognosis for patients. The widely used anti-diabetic drug Metformin has been reported to possess anti-cancer properties. Although it is believed that Metformin may exert its anti-cancer effects through indirect reduction of glucose and insulin levels, and directly activating the AMPK kinase and inhibiting downstream cancer-related pathways, the molecular mechanisms underlying its anti-cancer function in TNBC have yet to be fully elucidated. In this study, we investigated the role and mechanism of Metformin-mediated downregulation of oncogenic c-Met in MDA-MB-468 TNBC cells. Our results demonstrated greater sensitivity of MDA-MB-468 cells to Metformin compared to other breast cancer cell lines. Metformin-induced inhibition of MDA-MB-468 cell proliferation was correlated with the downregulation of c-Met at both protein and mRNA levels. Overexpression of c-Met in MDA-MB-468 cells using a lentiviral vector system rendered the cells resistant to Metformin, which was accompanied by the promotion of cancer stem cell stemness. Functionally, we demonstrated that c-Met induced activation of receptor tyrosine kinase (RTK) signaling pathways play a critical role in c-Met-modulated Metformin responsiveness. These novel findings highlight c-Met as a key regulator of Metformin-mediated inhibition of TNBC cell growth, suggesting that c-Met overexpression may be a critical factor contributing to metformin resistance. To this end, combination of Metformin with c-Met inhibitors could be a useful strategy to improve Metformin-mediated anti-cancer efficacies in TNBC. Citation Format: Dana M. Gant, Zhikun Ma, Amanda B. Parris, Xiaohe Yang. c-Met downregulation contributes to Metformin-induced inhibition of MDA-MB-468 triple negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1123.

Abstract 6185: Combining PARP inhibitor with cMET Inhibition overcomes PARP inhibitor resistance in epithelial ovarian cancer

Abstract Many studies have reported the efficacy of poly (ADP-ribose) polymerase (PARP) inhibitors in patients with epithelial ovarian cancer (EOC) with or without both germline/somatic BRCA mutations. However, resistance to PARP inhibitor occurs frequently in patients with advanced stage and recurrent. The receptor tyrosine kinase cMET, which is frequently overexpressed in EOC associates with PARP1 activity and cell survival pathway. Therefore, we investigated whether the combination of olaparib and savolitinib, a novel cMET inhibitor, could overcome PARP inhibitor resistance on resistant patient-derived xenografts (PDXs). Tumor tissues were obtained from patients with EOC operated at department of obstetrics and gynecology, Asan medical center, Seoul, South Korea. BRCA1 or BRCA2 mutated and cMET overexpressed tumors were selected and used for animal experiments. The tumor tissues were subcutaneous transplanted into right flank of NOD-scid IL2Rgammanull (NSG) mice. 60~90 days after transplantation, olaparib was administrated (80~100 mg/kg, daily, P.O.). Tumors were inhibited until volume decreased to 0~50 mm3. When the tumor volume was reached under 50 mm3, administration was stopped and tumors were allowed to regrowth. After tumor regrowth, to confirm resistance, administrated concentration of the olaparib was gradually increased 40 to 100 mg/kg (daily, P.O.). The resistant tumors were harvested and re-transplanted into 40 NSG mice. When tumor volumes reached at 100 mm3, mice were divided into 4 groups (Vehicle, Olapairb, Savolitinib, Combination) and olaparib (100 mg/kg, daily, P.O.) and savolitinib (25 mg/kg, daily, P.O.) were administrated. We established acquired resistant and innate resistant PDXs, which have BRCA mutation and cMET overexpression. These resistant models were used for evaluation of combined treatment of PARP inhibitor and cMET inhibitor. In case of the olaparib sensitive PDXs, tumor growth was suppressed to a similar level in combination group and olaparib single treatment group. Single treatment of cMET inhibitor also showed little inhibition in tumor growth. In case of the acquired resistant PDXs, tumor growth rate were highly increased in vehicle group than the sensitive PDXs. Contrary to sensitive group, combination treatment was more efficient to inhibit tumor growth rather than olaparib single treatment. The innate resistant PDXs were more tolerated to olapairb than the acquired resistant PDXs. Similar to acquired resistant PDXs, innate PDXs also showed rapid tumor growth in vehicle. As the acquired resistant PDXs, combination treatment was most efficient to inhibited tumor growth. In this study, cMET inhibition sensitized the resistant tumor to PARP inhibitor. These results indicated that savolitinib, novel cMET inhibitor, could have synergy with the PARP inhibitor for patients with PARP inhibitor resistant ovarian cancer. Citation Format: Min-Je Kim, Shin-Wha Lee, Young-Jae Lee, Su-Bin Park, Dong-Woo Kang, Yong-Man Kim. Combining PARP inhibitor with cMET Inhibition overcomes PARP inhibitor resistance in epithelial ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6185.

A phase 1 dose-escalation study of the ABN401 (c-MET inhibitor) in patients with solid tumors.

3105 Background: MET is a proto-oncogene encoding a receptor tyrosine kinase c-MET for hepatocyte growth factor (HGF). Dysregulated MET signaling by MET exon14 skipping, MET gene amplification and c-MET overexpression in cancer plays a critical role in the development of primary oncogenesis, acquired drug resistance and metastasis. This is a first-in-human trial, phase 1 dose-escalation study of the highly selective MET kinase inhibitor, ABN401. ABN401was evaluated in subjects with advanced solid tumors in South Korea and Australia. Methods: Patients with advanced solid tumors were enrolled in escalating dose cohorts using an accelerated titration design. ABN401 was orally administered daily with 21-day cycle. The primary objective was to evaluate safety and tolerability to define dose-limiting toxicity (DLT), maximum tolerated dose (MTD) according to CTCAE v5. Secondary objectives included pharmacokinetic, recommended phase II dose (RP2D), and preliminary efficacy assessments. Tumor assessment was determined using Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Results: Out of 28 screened patients, 16 patients with 6 different tumor types were treated with ABN401 at daily dose levels of 50, 100, 200, 400, 800 and 1200 mg, 15 patients were evaluated for DLT and one unevaluable. No DLT was observed in all 6 dose levels and the MTD has not been reached. No drug related grade ≥ 3 AEs were observed: only one drug-related SAE (transient peripheral edema) was reported. For treatment response, 5 patients with stable disease, and 2 with partial response were observed. These two patients with partial response had non-small cell lung cancer (NSCLC) with c-MET overexpression and had been treated with ABN401 for 10 and 18 months, respectively. Conclusions: ABN401 dosed up to 1200 mg QD was well tolerated with an acceptable safety profile and promising preliminary antitumor activity in patients with advanced solid tumors. The extension (pilot expansion) for additional efficacy assessment is under way at 800 mg daily dose with c-MET altered NSCLC patients in South Korea and Australia. In addition, a phase 2 expansion study is to start in the United States and South Korea. Clinical trial information: NCT04052971.

Phase 1/1b study of telisotuzumab vedotin (Teliso-V) + osimertinib (Osi), after failure on prior Osi, in patients with advanced, c-Met overexpressing, EGFR-mutated non-small cell lung cancer (NSCLC).

9013 Background: Osi (third-generation tyrosine kinase inhibitor) is a standard frontline treatment (Tx) for advanced/metastatic EGFR-mutated NSCLC. However, tumors invariably progress after an initial response, with c-Met protein overexpression (OE) often associated with acquired resistance. Second- and third-line Tx options are limited to chemotherapy-based regimens with limited efficacy and significant toxicities. Teliso-V (ABBV-399), an anti–c-Met antibody-drug conjugate, delivers a cytotoxic payload (monomethyl auristatin E) into c-Met OE tumor cells. In a phase 1/1b study (NCT02099058) in patients (pts) with c-Met OE NSCLC, Teliso-V alone or in combination with erlotinib demonstrated an acceptable safety profile and antitumor activity. Interim safety and efficacy data from the Teliso-V + Osi cohort (arm E) of this trial are presented. Methods: Pts (≥18 yr) with metastatic EGFR-mutated, c-Met OE (by central immunohistochemistry) NSCLC who had progressed on a prior Osi regimen were eligible. Pts received Teliso-V (IV Q2W) + Osi (oral; 80 mg QD). Teliso-V was evaluated at 1.6 mg/kg and, after review of safety data, escalated to 1.9 mg/kg (safety evaluation). An expansion cohort was opened at 1.9 mg/kg for pts who had received ≤2 prior lines of systemic therapy. Pharmacokinetics (PK) were assessed throughout the study. Pts received study Tx until disease progression, unacceptable toxicity, or for up to 24 months. Results: As of 20 Dec 2021, 25 pts received Teliso-V (1.6 mg/kg, n = 7; 1.9 mg/kg, n = 18) + Osi. Median age was 60.0 yr; 14 (58%) pts were on prior Tx with Osi for > 12 mo. No dose-limiting toxicities (grade [Gr] ≥3 non-hematologic or Gr 4 hematologic Tx-related adverse events [AEs]) were reported during the safety lead-in or evaluation phases. All-Gr AEs considered possibly related to Teliso-V occurred in 22/25 (88%) pts: the most common (≥20%) were peripheral sensory neuropathy (36%), nausea, and peripheral edema (20% each); Gr ≥3 AEs (> 5%) were anemia (12%) and peripheral motor neuropathy (8%). No Gr 5 events related to Tx were reported. PK of Teliso-V + Osi was similar to single-agent Teliso-V. Efficacy data (19/25 pts) are in the table. The overall objective response rate (ORR) was 58% (67% at 1.9 mg/kg). Conclusions: Teliso-V + Osi is well tolerated with an ORR of 58% (67% at 1.9 mg/kg) in pts with c-Met OE NSCLC who progressed on prior Osi. Clinical trial information: NCT02099058. [Table: see text]

Telisotuzumab vedotin (Teliso-V) monotherapy in patients (pts) with previously treated c-Met–overexpressing (OE) advanced non-small cell lung cancer (NSCLC).

9016 Background: Teliso-V is an antibody-drug conjugate composed of a c-Met antibody (ABT-700) and a microtubule inhibitor (monomethyl auristatin E). The phase 2 M14-239 trial (LUMINOSITY, NCT03539536) aims to identify the c-Met OE NSCLC populations best suited to Teliso-V (Stage 1) and expand selected groups for further evaluation of efficacy (Stage 2). In Stage 1, pts were enrolled into cohorts defined by histopathology (non-squamous [NSQ] or squamous [SQ]) and EGFR mutation status (mutant or wild type [WT]); NSQ cohorts were further divided in groups on the basis of c-Met expression (high or intermediate). Updated data from the fourth interim analysis (IA4) are presented. Methods: Pts had locally advanced/metastatic NSCLC, ≤2 prior lines of systemic therapy, ≤1 line of chemotherapy, and tumors that were c-Met OE by central immunohistochemistry (IHC; Ventana; Tucson, AZ). c-Met OE was defined for the NSQ cohort as ≥25% 3+ by IHC (high, ≥50% 3+; intermediate, 25 to <50% 3+) and for the SQ cohort as ≥75% 1+ by IHC. The planned enrollment was up to approximately 150 pts in Stage 1 and 160 pts in Stage 2. Teliso-V was dosed at 1.9 mg/kg IV Q2W. The primary endpoint is objective response rate (ORR) by independent central review. Secondary endpoints include duration of response (DOR). Results: As of data cutoff (27 May 2021), 136 pts were treated with Teliso-V; 122 were evaluable for ORR. ORR was 36.5% in the NSQ EGFR WT cohort (52.2% in c-Met high group and 24.1% in c-Met intermediate group), but was modest in the NSQ EGFR mutant and SQ cohorts. Efficacy data in groups/cohorts are in the Table. The most common any-grade adverse events (AEs) were peripheral sensory neuropathy (25.0%), nausea (22.1%), and hypoalbuminemia (20.6%). Grade 5 AEs considered possibly related to Teliso-V occurred in 2 pts (sudden death and pneumonitis in 1 pt each in the SQ cohort). Conclusions: Teliso-V demonstrated a promising ORR in pts with previously treated c-Met OE NSQ EGFR WT NSCLC; this cohort is currently expanding in Stage 2. ORR was modest in the cohorts of pts with c-Met OE NSQ EGFR mutant NSCLC and with c-Met OE SQ NSCLC; both cohorts have now met the protocol-specified stopping criteria and are no longer enrolling. The safety profile observed was consistent with IA3. Clinical trial information: NCT03539536. [Table: see text]

Metformin-induced downregulation of c-Met is a determinant of sensitivity in MDA-MB-468 breast cancer cells

Metformin, the widely used anti-diabetic drug, is emerging as a promising anti-cancer agent. However, response variation among different tumors remains a significant challenge. Hence, identification of the factors that determine metformin sensitivity is of greatest significance for its clinical implementation. In this study, we showed that MDA-MB-468 cells were most sensitive among the five breast cancer cell lines tested. We found that metformin-induced inhibition of MDA-MB-468 cells was correlated with downregulation of c-Met at both protein and mRNA levels. To understand the functional significance of c-Met downregulation in metformin-mediated tumor inhibition, we established control and c-Met overexpressing sublines of MDA-MB-468 cells (468/C and 468/Met) using lentiviral expression system. We demonstrated that overexpression of c-Met significantly attenuated metformin induced inhibition of MDA-MB-468 cells. Metformin-induced inhibition of ALDH1+ cells, which are enriched with cancer stem cells, was also abrogated in 468/Met cells as compared to 468/C cells. Signal transduction analysis of the paired cell lines indicated that c-Met-induced activation of STAT3 and AKT1, and upregulation of Gab1 are related to c-Met-modulated metformin responsiveness. These findings highlight c-Met as a potential key regulator of metformin-mediated inhibition of proliferation and stemness of breast cancer cells, indicating that c-Met overexpression may be a critical factor contributing to metformin resistance. The data also suggest that combination of metformin with c-Met inhibitors could be a useful strategy to improve metformin-mediated anti-cancer efficacies in breast cancer treatment.

183: MOLECULAR CHARACTERIZATION OF ESOPHAGEAL ADENOCARCINOMAS (EACS) AND ITS PROGNOSTIC IMPACT

Abstract Background and aim Esophageal adenocarcinomas (EACs) have an increasing incidence and a poor prognosis. While gastric cancer molecular subtypes are well characterized with 4 categories: EBV+, Microsatellite instability (MSI), Genomically stable (GS), Chromosomal instability (CIN), there is less data available on EACs. Often compared to stomach, recent literature only describes CIN subtype in EACs, while our clinical experience suggests greater heterogeneity. The aims of our study were (i) to characterize EACs from a molecular perspective based on a large clinico-biological database and (ii) compare our clinico-pathological data with molecular results to analyze their prognostic impact. Methods 516 patients underwent a transthoracic esophagectomy at the University Hospital of Lille. All HES staining slides from surgical specimen was reviewed, followed by a tissue microarrays analysis. Molecular subtypes were determined by immunohistochemistry (IHC) (MMR proteins for the deficient MMR (dMMR) and MSI-PCR for the dMMR/MSI subtype, E-cadherin for the GS subtype, HER2, C-MET and KRAS for the CIN subtype), and in situ hybridization (EBV+). Results In our series, 290 EACs are located on the esogastric junction (Siewert I and II), and 226 are above. Our current analysis highlighted one patient EBV+ and 26 dMMR status (9%). Interestingly, we observed discordances between MSI-PCR and IHC results in a third of cases (n = 8), suggesting possible modifications induced by pre-operative treatment. Our results about CIN and GS subtypes are consistent with literature with a loss of E-cadherin expression in 22 tumors (15%). An overexpression of HER2, C-MET and KRAS was noticed in 12 (8%), 41 (27%) and 13 (9%) tumors, respectively. We observed a trend toward better survival in the dMMR/MSI group comparing to GS subtype (90% vs 40% at 60 months, P = 0.07). Further analyses of the prognostic impact are in progress. Conclusion Our study highlights the presence of biomarkers in EACs, defining at least 4 molecular subtypes, partly overlapping to those already described in gastric cancer. Interestingly, finding of EBV+ and MSI tumors was unexpected and never described elsewhere in previous genomic characterization. The prognostic impact of these 4 subtypes underlined the necessity of routine molecular characterization to adapt the therapeutic strategy.

Phase Ia/Ib Study of the Selective MET Inhibitor, Savolitinib, in Patients with Advanced Solid Tumors: Safety, Efficacy, and Biomarkers.

Savolitinib has shown good tolerability and preliminary efficacy, but efficacy biomarkers require investigation. The main purpose of this study was to confirm in Chinese patients the recommended phase II dose (RP2D) of savolitinib and to explore overall benefit in tumors bearing c-Met aberration. This was an open-label, multi-center, 2-part phase I study. A starting dose of 600 mg QD was initiated in the escalation phase, utilizing a 3+3 design with repeated QD and BID dosing. In the dose expansion phase, we enrolled patients with gastric cancer and non-small cell lung cancer (NSCLC) with documented c-met aberration into 5 cohorts to further explore biomarkers. c-Met overexpression and amplification were assessed by immunohistochemistry and FISH, respectively. The safety analysis set included 85 patients. Only one dose-limiting toxicity (grade 3 fatigue) was reported in the 600 mg BID dosing group. The most frequent treatment-related adverse events were nausea (29.4%), vomiting (27.1%), and peripheral edema (21.2%). Notably, in gastric cancer, response was only observed in patients with MET amplification (copy number 9.7-18.4), with an objective response rate of 35.7% and a disease control rate of 64.3%. For patients with NSCLC bearing a MET exon 14 skipping mutation, obvious target lesion shrinkage was observed in 2 of 4 patients, although PR was not achieved. The RP2D of savolitinib was established as 600 mg QD or 500 mg BID in Chinese patients. The promising response observed in patients with gastric cancer with c-met amplification and NSCLC with MET exon 14 skipping mutation warrants further investigation. NCT0198555.

MiR-300 Alleviates Cell Proliferation and Migration and Facilitates Cell Apoptosis by Targeting c-Met in Gastric Cancer.

c-Met is a potent oncogene, whose aberrant activation has not been fully clarified. In this study, we discover the biological function of miR-300 in gastric cancer (GC) carcinogenesis and the underlying mechanism. The overexpression, oncogenic functions, and survival analysis of c-Met in GC tissues and cells were firstly determined. miRNAs that potentially targets c-Met were then predicted by bioinformatics. The expression levels of candidate miR-300 in GC tissue pairs were investigated. Pearson analysis revealed a negative relation between miR-300 and c-Met expressions. miR-300 and c-Met expression levels were determined in three GC cell lines (MKN-45, SGC-7901, and AGS) as well. Reduced miR-300 led to increase c-Met levels. Luciferase report assay demonstrated a direct binding site of miR-300 in the 3' untranslated region (3′UTR) of c-Met. Finally, the regulatory role of miR-300 on MKN-45 cells was studied by cell proliferation, migration, and apoptosis assays. Overexpression of miR-300 attenuated viability and migration and accelerated apoptosis in MKN-45. We also induced a rescue experiment with c-Met overexpression plasmid and finally proved that miR-300 exerted a suppressing role on MKN-45 proliferation and migration but promoted MKN-45 apoptosis by directly inhibiting c-Met. This study provides a novel insight into the targeted drug development for GC therapies.

Licochalcone A Promotes the Ubiquitination of c-Met to Abrogate Gefitinib Resistance.

Met proto-oncogene (MET) amplification and tyrosine-protein kinase Met (c-Met) overexpression confer gefitinib resistance in non-small cell lung cancer (NSCLC). The natural product Licochalcone A (Lico A) exhibits a broad range of inhibitory effects against various tumors. However, the effects of Lico A on c-Met signaling and gefitinib resistance in NSCLC remain unclear. In the present study, Lico A efficiently overcame gefitinib-acquired resistance in NSCLC cells by suppressing c-Met signaling. Lico A decreased cell viability and colony formation dose-dependently and impaired in vivo tumorigenesis of gefitinib-resistant HCC827 and PC-9 cells. Furthermore, Lico A induced intrinsic apoptosis and upregulated the protein expression levels of cleaved poly (ADP-ribose) polymerase and cleaved caspase 3. Lico A promoted the interaction between c-Met and E3 ligase c-Casitas B-lineage lymphoma (Cbl), which enhanced c-Cbl-mediated c-Met ubiquitination and degradation. Depletion of c-Cbl compromised Lico A-induced c-Met ubiquitination and its inhibitory efficacy in gefitinib-resistant NSCLC cells. Taken together, the results suggest that Lico A is a promising antitumor agent that might be used to overcome c-Met overexpression-mediated gefitinib resistance in NSCLC cells.

An updated patent review of small-molecule c-Met kinase inhibitors (2018-present)

Introduction c-Met tyrosine kinase receptor is a high-affinity ligand of hepatocyte growth factor (HGF). c-Met is widely expressed in a variety of normal human tissues, but it exhibits abnormally high expression, amplification or mutation in tumor tissues such as lung cancer, gastric cancer, and breast cancer. Therefore, the use of c-Met as a target can achieve the inhibition of a series of abnormal physiological processes such as tumourigenesis, development and metastasis. A number of small molecule tyrosine kinase inhibitors targeting c-Met have been successfully marketed. Areas covered This article reviews recent advances in patented c-Met small molecule inhibitors and their inhibitory activity against various cancer cells from 2018 to date. Expert opinion To date, small molecule inhibitors targeting c-Met have demonstrated impressive therapeutic efficacy in the clinical setting. Most recent patents have focused on addressing the direction of c-Met amplification and overexpression. Despite the great success in the development of selective c-Met inhibitors, the effects of bypass secretion and mutagenesis have led to a need for new c-Met small molecule inhibitors that are safe, efficient, selective and less toxic with novel structures and effective against other targets.

Therapeutic efficacy of FASN inhibition in preclinical models of HCC.

Aberrant activation of fatty acid synthase (FASN) is a major metabolic event during the development of HCC. We evaluated the therapeutic efficacy of TVB3664, a FASN inhibitor, either alone or in combination, for HCC treatment. The therapeutic efficacy and the molecular pathways targeted by TVB3664, either alone or with tyrosine kinase inhibitors or the checkpoint inhibitor anti-programmed death ligand 1 antibody, were assessed in human HCC cell lines and multiple oncogene-driven HCC mouse models. RNA sequencing was performed to elucidate the effects of TVB3664 on global gene expression and tumor metabolism. TVB3664 significantly ameliorated the fatty liver phenotype in the aged mice and AKT-induced hepatic steatosis. TVB3664 monotherapy showed moderate efficacy in NASH-related murine HCCs, induced by loss of phosphatase and tensin homolog and MET proto-oncogene, receptor tyrosine kinase (c-MET) overexpression. TVB3664, in combination with cabozantinib, triggered tumor regression in this murine model but did not improve the responsiveness to immunotherapy. Global gene expression revealed that TVB3664 predominantly modulated metabolic processes, whereas TVB3664 synergized with cabozantinib to down-regulate multiple cancer-related pathways, especially the AKT/mammalian target of rapamycin pathway and cell proliferation genes. TVB3664 also improved the therapeutic efficacy of sorafenib and cabozantinib in the FASN-dependent c-MYC-driven HCC model. However, TVB3664 had no efficacy nor synergistic effects in FASN-independent murine HCC models. This preclinical study suggests the limited efficacy of targeting FASN as monotherapy for HCC treatment. However, FASN inhibitors could be combined with other drugs for improved effectiveness. These combination therapies could be developed based on the driver oncogenes, supporting precision medicine approaches for HCC treatment.

MicroRNA-128-3p Mediates Lenvatinib Resistance of Hepatocellular Carcinoma Cells by Downregulating c-Met.

ObjectiveLenvatinib is a first-line multikinase inhibitor for advanced hepatocellular carcinoma (HCC), but resistance to the drug remains a major hurdle for its long-term anti-cancer activity. This resistance is thought to be due to overexpression of c-Met. This study aims to identify potential upstream microRNAs (miRNAs) that regulate c-Met, investigate the underlying mechanisms, and seek potential strategies that may reverse such resistance.MethodsLenvatinib-resistant HCC (LR-HCC) cells were established from human HCC Huh7 and SMMC-7721 cells. Assays of cell proliferation, cell cycle distribution, apoptosis, RT-qPCR, Western blot analysis and immunohistochemistry were employed. Potential miRNAs were screened by miRNA-target prediction tools and their regulatory effects were evaluated by luciferase reporter assays. Xenograft tumor models were used to evaluate the therapeutic effects.ResultsLR-HCC cells were refractory to lenvatinib-induced growth inhibition and apoptosis in vitro and in vivo. Sustained exposure of cells to lenvatinib resulted in increased expression and phosphorylation of c-Met, and c-Met inhibition enhanced the effects of lenvatinib in suppressing LR-HCC cells. Among eleven miRNA candidates, miR-128-3p displayed the most vigorous activity to negatively regulate c-Met and was downregulated in LR-HCC cells. MiR-128-3p mimics inhibited proliferation and induced apoptosis of LR-HCC cells, and enhanced the effects of lenvatinib in cell culture and animal models. MiR-128-3p and c-Met participate in the mechanisms underlying lenvatinib resistance through regulating Akt that mediates the apoptotic pathway and ERK (extracellular-signal-regulated kinase) modulating cell cycle progression.ConclusionThe present results indicate that the miR-128-3p/c-Met axis may be potential therapeutic targets for circumventing lenvatinib resistance in HCC and warrant further investigation.

ABHD5 inhibits YAP-induced c-Met overexpression and colon cancer cell stemness via suppressing YAP methylation

Cancer stemness represents a major source of development and progression of colorectal cancer (CRC). c-Met critically contributes to CRC stemness, but how c-Met is activated in CRC remains elusive. We previously identified the lipolytic factor ABHD5 as an important tumour suppressor gene in CRC. Here, we show that loss of ABHD5 promotes c-Met activation to sustain CRC stemness in a non-canonical manner. Mechanistically, we demonstrate that ABHD5 interacts in the cytoplasm with the core subunit of the SET1A methyltransferase complex, DPY30, thereby inhibiting the nuclear translocation of DPY30 and activity of SET1A. In the absence of ABHD5, DPY30 translocates to the nucleus and supports SET1A-mediated methylation of YAP and histone H3, which sequesters YAP in the nucleus and increases chromatin accessibility to synergistically promote YAP-induced transcription of c-Met, thus promoting the stemness of CRC cells. This study reveals a novel role of ABHD5 in regulating histone/non-histone methylation and CRC stemness.

Overexpression of c-Met is Associated with Poor Prognosis in Glioblastoma Multiforme: A Systematic Review and Meta-Analyses.

Objective:The aim of this study is to evaluate the association of c-Met overexpression with survival of glioblastoma multiforme (GBM) patients. Methods:A systematic review with meta-analyses was conducted on related articles from PubMed, EBSCOhost, Scopus, and Cochrane databases with last updated search on October 31, 2020. A total of 7 studies regarding c-Met overexpression and overall survival (OS) and/or progression free survival (PFS) are included in this study. Results:All studies used immunohistochemistry to examine the expression of c-Met protein. The results showed that the positive rate of c-Met overexpression was detected in approximately 33,9% - 60,5% of GBM patients. c-Met overexpression was related to worse OS (HR: 1,74; 95% CI: 1,482-2,043; Z=6,756; p<0,001) and PFS (HR: 1,66; 95% CI: 1,327-2,066; Z=4,464; p<0,001) in GBM patients. Low heterogeneity of subjects was found in both OS and PFS analyses, I2 values were 7,8% and 0,0%, respectively. Conclusion:In conclusion, c-Met overexpression is significantly related to shorter OS and PFS in GBM patients, so c-Met can be considered as a potential prognostic indicator in GBM.