MET amplification

Notably, combined inhibition of HGF/MET signaling and Asn metabolism produces greater antitumor activity than either monotherapy. Together, these data delineate an HGF/MET → ETV4 → MET/ASNS → asparagine → iCAFs and iCAF-like HSCs → HGF circuit that links signal amplification, metabolic reprogramming, and niche conditioning, and provide a rationale for therapeutic strategies co‑targeting HGF/MET and Asn pathways in advanced CRC.

While third-generation tyrosine kinase inhibitors (TKIs) like osimertinib have long served as the frontline standard, the emergence of heterogeneous resistance mechanisms requires more robust therapeutic strategies. This review evaluates the clinical impact of the MARIPOSA trial, which demonstrated the superior efficacy of combining the bispecific antibody amivantamab with lazertinib...Furthermore, we explore the diversifying landscape of second-line interventions, including the rise of antibody-drug conjugates (ADCs) like Sac-TMT and patritumab-deruxtecan, dual PD-1/VEGF inhibitors, and novel fourth-generation TKIs. By integrating preclinical insights on drug-tolerant persister cells with late-phase clinical data, this article outlines a future for EGFR-mutant NSCLC management defined by precision sequencing and the proactive mitigation of molecular resistance.

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.

Amivantamab-lazertinib reduces common resistance mechanisms (e.g., EGFR/MET) versus osimertinib, suggesting that this regimen is changing the underlying biology of EGFR-mutant disease, contributing to both first- and second-line long-term efficacy outcomes.

RET fusions represent a rare mechanism of acquired resistance in EGFR-mutant NSCLC. Combined RET and EGFR inhibition may offer clinical benefit, particularly in patients with co-occurring alterations. Personalized ddPCR-based liquid biopsy is a promising tool for real-time, non-invasive monitoring of treatment response and resistance evolution.

Molecular testing of effusion samples is feasible even at low fluid volumes, provided tumor cellularity is adequate. Prioritizing tumor fraction over volume ensures a higher likelihood of successful molecular analysis. Effusion-based NGS reliably identifies actionable alterations with diagnostic and prognostic relevance. Male patients, smokers, concurrent or primary presentation with MPE, and those with TP53 mutations had poorer outcomes.

Next-generation sequencing may be suggested for refractory malignant melanoma. Crizotinib may be used to treat malignant melanoma with MET amplification.

P2, N=19, Not yet recruiting, Shanghai Chest Hospital

Serial cell lines from a patient with EGFR L858R and MET amplification (PE5345), after resistance to osimertinib and capmatinib through gradual escalation of drug exposure in vitro (PE5345 os/cp R) and after clinical resistance to osimertinib and capmatinib (PE5867), were propagated...Osimertinib plus trametinib reversed resistance. PE5345 os/cp R overexpressed EGFR, which was inhibited by afatinib...Amivantamab induced significant ADCC against both MET-amplified EGFR TKI-resistant cancer and resistant cells after dual EGFR/MET inhibition. Understanding resistance mechanisms may provide clues for subsequent therapy.

The disease proved refractory to multiple lines of therapy, including platinum-based chemotherapy, immunotherapy, intrathoracic instillation and a subsequent individualized regimen comprising intraperitoneal cisplatin plus sintilimab for local disease control and potential immunomodulation synergized with oral anlotinib. It illustrates that rare but actionable genomic alterations, such as MET amplification, can be identified through liquid or tissue biopsy and can inform successful targeted treatment strategies, even in a tumor type where such alterations are uncommon. Histological classification combined with molecular profiling remains pivotal for personalized oncology.

The clinical future lies in interception: leveraging liquid biopsies for early detection, targeting both tumor-intrinsic vulnerabilities and permissive metastatic niches and adapting therapy dynamically to anticipate resistance. Understanding this genomic odyssey is essential for transforming mCRC into a controllable chronic condition.