MET-H

We established HER3-and/or MET-KO SW1116 cell lines, and HER3/MET-double KO resulted in the inhibition of in vitro cell proliferation and in vivo tumor growth in nude mice by SW1116 cells. Furthermore, the combination of patritumab, an anti-HER3 fully human mAb, and PHA665752, a MET inhibitor, markedly inhibited in vitro cell proliferation, 3D-colony formation, and in vivo tumor growth in nude mice by SW1116 cells The dual targeting of HER3/MET has potential as CRC therapy.

Furthermore, CCN4 cells also exerted the prominent tumor-inhibitory effect on xenograft tumor growth. Collectively, this study suggests that DAP10 is a potent stimulator in CAR structure for NK cell activation, and CCN4-based immunotherapy may represent a promising strategy for the treatment of c-Met-positive LUAD.

Our findings reveal that HGF and TNFα are critical for the crosstalk between breast cancer cells and CAFs in the TME and that the HGF/c-Met signaling pathway is a promising therapeutic target for radiosensitizing breast cancer.

In our series, high c-MET expression correlated with poor survival outcomes. Further studies are warranted to validate the clinical relevance and applicability of c-MET as a prognostic factor in ER+/HER2- early BC.

Magnetic activated cell sorting was used to separate the CD44v6+ from CD44v6- cells, and Met levels were regulated using lentiviral particles and the selective Met inhibitor, PHA665752...Further, a cJun binding site was identified 1700 bp upstream of the Nanog transcription start site and mutation of the cJun binding site reduced Nanog expression. In conclusion, the HGF/Met signaling pathway is important for maintenance of stemness in CD44v6+ HCC cells by enhancing expression of cJun, which binds 1700 bp upstream of the Nanog transcription start site.

In this FIH phase I trial, CT053PTSA was well tolerated and had a satisfactory safety profile. Further trials evaluating the clinical activity of CT053PTSA are ongoing.

No abstract available

Teliso-V plus erlotinib showed encouraging antitumor activity and acceptable toxicity in EGFR TKI-pretreated patients with EGFR-M+, c-Met+ NSCLC.

In this study, simple NGS output data analysis from RNA-based NGS assay allowed reliable prediction of MET highamplification status in NSCLC. Although copy number variation analysis is usually restricted to DNA panels, this study shows that focused analysis can be useful to triage and select samples with candidate MET gene amplifications from an RNA-based NGS assay.

Targeting SIGLEC15 may offer a potential novel therapeutic opportunity for THCA patients. However, the detailed exact cellular mechanisms of SIGLEC15 in THCA still needed to be elucidated by further studies.

P2, N=3, Active, not recruiting, National Cancer Institute (NCI) | N=169 --> 3 | Trial completion date: Dec 2022 --> Sep 2023 | Trial primary completion date: Dec 2022 --> May 2022

P2, N=43, Completed, Armando Santoro, MD | Unknown status --> Completed

Given the small sample size, a larger study is needed to verify this result. CohortMET GCN by FISHParameterFocal METampNonfocal METampPts analyzedAll pts in cohortC1a≥10N14152969ORR, n (%)8 (57)2 (13)10 (34)20 (29)C1b≥6 and <10N3293242ORR, n (%)2 (67)1 (3)3 (9)5 (12)C2≥4 and <6N0313154ORR, n (%)-2 (6)2 (6)5 (9)C3<4N1202130ORR, n (%)0 (0)1 (5)1 (5)2 (7)

We propose that a high MET pCN and/or ApCN, together with the absence of overlapping oncogenic drivers and small MET amplicon size, will enrich for patients most likely to derive benefit from MET targeted therapy.

Wolf et al NEJM 2020; https://doi.org/10.1056/NEJMoa2002787; 3. Koshihara et al Nat Commun 2013; 4:2612.

Transcriptomic classification of cancer cell lines based on MET expression showed that response to the PARP inhibitor (PARPi) olaparib is poorer in MET overexpressing cell lines...Given the role played by NuMA in mitosis, data show that the latter is affected by MET and PARP inhibition in cells with haploinsufficient ATM. This is important as ATM heterozygous mutation is frequently found in human cancer and in lung carcinomas in particular.

P1/2, N=344, Recruiting, Apollomics Inc. | N=201 --> 344 | Trial completion date: Dec 2022 --> Nov 2026 | Trial primary completion date: Dec 2022 --> Mar 2026

P2, N=142, Recruiting, National Cancer Institute (NCI) | Trial completion date: May 2022 --> May 2023 | Trial primary completion date: May 2022 --> May 2023

DFS observed with osimertinib in patients with early-stage EGFR-mutated tumors supports evaluation of other tyrosine kinase inhibitors (TKIs) in the neoadjuvant and adjuvant settings. Following treatment, there will be a 2-year survival follow-up. Enrollment has started; expected first patient first visit: March 31, 2022.

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.

Moreover, c-Met-28-137-3ζ CAR-T cells eradicated HCC more effectively in xenograft tumor models compared with the control groups. This study suggests that 3 -generation c-Met CAR-T cells are more effective in inhibiting c-Met-positive HCC cells than 2 -generation c-Met CAR-T cells, thereby providing a promising therapeutic intervention for c-Met-positive HCC.

MACC1, c-Met, and cyclin D1 proteins are closely related to the occurrence and development of esophageal squamous cell carcinoma. MACC1 may affect the prognosis of ESCC by regulating the expression of the c-Met/cyclin D1 axis.

In bevacizumab-treated women diagnosed with EOC, high c-MET/VEGFR-2 co-localisation on tumour tissue and the VEGFR-2 rs2305945 G/G variant, which may be biologically related, were associated with worse survival outcomes.

DFS observed with osimertinib in patients with early-stage EGFR-mutated tumors supports evaluation of other tyrosine kinase inhibitors (TKIs) in the neoadjuvant and adjuvant settings. Following treatment, there will be a 2-year survival follow-up. The expected first patient first visit is December 30, 2021.

In addition, network-based prioritization showed co-functional enrichment of c-Met and myoferlin, suggesting a novel regulatory function of myoferlin in c-Met signaling. This study indicates that c-Met and EPHA7 might be useful prognostic biomarkers, and the presumed myoferlin/c-Met pathway could be a novel therapeutic target in ccRCC.

In summary, the results from this study indicated that AFP may promote GC progression by stimulating MACC1. This finding may help illustrating the aggressive behaviors of GC in patients with high AFP serum level and AFP-GC.

P2, N=169, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2021 --> Dec 2022 | Trial primary completion date: Dec 2021 --> Dec 2022

Common adverse events with tivantinib treatment include neutropenia, ascites, rash, and anemia, etc. Several factors may contribute to the inconsistency between the phase 2 and phase 3 studies of tivantinib, including the sample size, drug dosing, study design, and the rate of MET-High. In the future, high selective MET inhibitors combined with a biomarker-driven patient selection may provide a potentially viable therapeutic strategy for patients with advanced HCC.

P2, N=44, Not yet recruiting, Guangdong Association of Clinical Trials

EMI-137, binds specifically to the human c-Met protein, is safe, and with further refinement, shows potential for application in fluorescence-guided surgery.

However, c-MET-high in the primary tumors was not significantly associated with longer survival compared with c-MET-low tumors. Further studies are required to investigate c-MET as potential molecular marker of progression and to test the possibility of its incorporation as a new therapeutic target.

Gene set enrichment analysis (GSEA) results indicated significant up-regulation of the immune response-related pathways in the MET-amplification group. Our results suggest that MET amplification may be a novel predictive marker for immunotherapy efficacy in NSCLC.

DNA repair gene germline mutation rates are low in an academic biobank cohort of localized PrCa patients, particularly among individuals of AFR genetic ancestry. Mutation rates in genes with published evidence of association with PrCa exceed 2.5% only in high-risk, very-high-risk localized, and node-positive PrCa patients. These findings highlight the importance of risk stratification in localized PrCa patients to identify appropriate patients for germline genetic testing.

One in five patients were classified as high risk according to mE criteria, although oncologists considered additional factors to categorize patients as high risk level in their daily practice. Consequently, many patients of L/M risk according to mE criteria could still be considered as high risk by their physicians, as suggested by nearly half of patients receiving ChT treatment as adjuvant therapy.

Furthermore, diabody-mp, which had a higher c-Met binding affinity, showed better anti-tumoral activity than diabody-pm, which had a lower c-Met binding affinity. In conclusion, bispecific anti-PD-1/c-Met diabody-mp, with high c-Met-associated affinity, inhibited tumor growth by activating T cells, suggesting its therapeutic potential for c-Met-positive solid tumors.

No abstract available

Akt induced the activation of JNK through the PI3K/Akt and JNK signaling pathways. HGF upregulates MMP9 through the activation of the PI3K/Akt and JNK signaling pathways in SCCHN cells.

In a cynomolgus monkey toxicology study, METxMET-M114 was well tolerated at a dose that provides circulating drug concentrations that are sufficient for maximal antitumor activity in mouse models. Our findings suggest that METxMET-M114, which takes advantage of the unique trafficking properties of our METxMET antibody, is a promising candidate for the treatment of MET-overexpressing tumors, with the potential to address some of the limitations faced by the MET function blockers currently in clinical use.

Our study reveals a new role for tumor-derived IL-6 in hijacking the HSPC differentiation program toward prometastatic MDPs that functionally differentiate into immunosuppressive monocytes to support the metastatic switch.

Capmatinib 400 mg bid in combination with gefitinib 250 mg qd was well-tolerated and showed encouraging clinical activity in patients with EGFR-mutant and MET-dysregulated NSCLC.