MET overexpression

MET amplification alters the balance of EGFR/MET/ERBB3 dimerization, leading to a shift in signaling dependence from EGFR to MET. These findings provide insight into therapeutic strategies for EGFR-mutated NSCLC.

Primary endpoint is Objective Response Rate (ORR) by Simon two-stage design. This study will provide evidence for vebreltinib combined with PD-1-based immunotherapy and improve understanding of advanced CCS management.Clinical trial registration: www.clinicaltrials.gov identifier is NCT07153887.

Crizotinib showed no significant difference in progression-free survival (PFS) or overall survival (OS) between first-line and post-chemotherapy use (PFS: p = 0.803; OS: p = 0.761). For second-generation ALK-TKIs, first-line treatment had numerically longer PFS compared to post-chemotherapy (alectinib: 41 vs 24 months; ceritinib: 30 vs 8 months), but these differences were not statistically significant after adjustment (p = 0.120 and 0.284, respectively)...Among patients treated with alectinib, there appears to be a trend toward shorter PFS and OS in those with MET overexpression. In a limited number of matched samples, PD-L1 expression did not change significantly after TKI resistance, although a slight increase was observed.

Teliso-V monotherapy 1.9 mg/kg elicited durable responses, irrespective of the type of previous therapy received, and maintained a manageable safety profile in patients with c-Met protein overexpressing EGFR wild-type, nonsquamous NSCLC. NCT03539536.

Free energy of binding calculations using the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) method supported these findings, with D4 showing the most favourable interaction, dominated by Van Der Waals and electrostatic contributions from key catalytic amino acid. Our research, with further experimental validation, could be helpful to support that certain MET inhibitors, especially D4, are promising competitive inhibitors of EGFRwt, offering potential for the development of new therapeutic strategies targeting EGFRwt-driven cancers.

P3, N=412, Active, not recruiting, Hutchison Medipharma Limited | Trial completion date: Aug 2026 --> May 2028 | Trial primary completion date: Aug 2026 --> May 2028

These results indicate c-Met protein overexpression can be assessed before or after treatment since most patients maintain consistent c-Met status. As targeted therapies may elevate c-Met overexpression over time, retesting may be necessary in those with an oncogenic driver alteration initially diagnosed as c-Met negative.

Moreover, comprehensive in vitro and in vivo experiments demonstrate that nitidine significantly inhibits tumor progression through an LRPPRC-MET-G4-dependent mechanism. Collectively, our study suggests an epigenetic regulatory mechanism involving LRPPRC-MET-G4-mediated MET upregulation and provides a promising therapeutic strategy for MET-driven tumors using molecular glues that target the LRPPRC-MET-G4 interface.

The AMPK-FOXO1-CALB2 axis mediates MET-induced mitochondrial dysfunction and apoptosis, providing a mechanistic basis for MET to overcome progesterone resistance in ECC.

Given the importance of plasma membrane-associated MET in initiating its canonical signaling cascades, as well as the demonstrated non-canonical signaling from nuclear localized MET in different tumor cell types and in response to various environmental stimuli, we developed assay capability to measure levels of pY1235MET and total MET within the plasma membrane or nucleus; these assays enable future explorations of the biological and clinical relevance of MET subcellular localization patterns. Finally, using tissue microarrays of over 50 resected tumor specimens from patients with colorectal carcinoma or non-small cell lung cancer, we demonstrated that tumor levels of pY1235MET do not always track total MET expression, suggesting that measurement of activated MET in tumor could hold potential as an independent biomarker to identify additional patients who might benefit from MET-directed targeted therapy-beyond those with tumor MET amplification, MET overexpression, or established MET-activating mutations.

Vebreltinib plus an EGFR-TKI demonstrates favorable efficacy and manageable safety in real-world NSCLC patients with MET-driven resistance, with notable intracranial activity. Immunohistochemistry 3 + may serve as a practical predictive biomarker.

While accelerated approval underscores its therapeutic promise, long-term positioning will depend on confirmatory trials, refinement of biomarker testing, and optimization of patient selection. If validated, this strategy may redefine later-line treatment expectations by aligning cytotoxic payload delivery with biologically enriched disease subsets.