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Background: In EGFR-mutant and MET-amplified lung cancer resistant to EGFR inhibitors, double blockade of EGFR and MET is considered as a reasonable strategy despite increasing toxicity. This study evaluated the single MET inhibition in these specific tumours.

Methods: We investigated the efficacy of a single MET inhibitor in EGFR-mutant, MET-amplified lung cancer cells (HCC827GR) and the matched clinical cases and patient-derived cells. Acquired resistance mechanisms to single MET inhibitor were further explored.

Results: Single MET inhibitor sufficiently inhibited the EGFR downstream signalling and proliferation in the HCC827GR cells. The MET-inhibitor-sensitive clones had similar EGFR mutation allele frequency as the MET-inhibitor-resistant clones. The patients with EGFR-mutant, MET-amplified lung cancer resistant to EGFR inhibitors showed definite response to single MET inhibitor but the response duration was not durable. The MET gene copy number in their plasma circulating tumour DNA was significantly decreased during the treatment and was not re-increased after progression. In the cells resistant to single MET inhibitor, the EGFR pathway was reactivated, and gefitinib alone successfully suppressed their growth.

Conclusions: Single MET inhibition produced a short-lived response in EGFR-mutant and MET-amplified lung cancer. A further study of a novel combination therapy schedule is needed to achieve long-lasting efficacy and less toxicity.

Titel:	Single targeting of MET in EGFR-mutated and MET-amplified non-small cell lung cancer.
Autor/in / Beteiligte Person:	Choi, YR ; Kang, EH ; Kim, S ; Park, SY ; Han, JY ; Lee, Y
Link:	View record at Springer (Volltext)
Zeitschrift:	British journal of cancer, Jg. 128 (2023-06-01), Heft 12, S. 2186-2196
Veröffentlichung:	2002- : London : Nature Publishing Group on behalf of Cancer Research UK ; <i>Original Publication</i>: London, Lewis., 2023
Medientyp:	academicJournal
ISSN:	1532-1827 (electronic)
DOI:	10.1038/s41416-023-02264-4
Schlagwort:	Humans Drug Resistance, Neoplasm genetics ErbB Receptors genetics ErbB Receptors metabolism Gefitinib Protein Kinase Inhibitors pharmacology Protein Kinase Inhibitors therapeutic use Mutation Cell Line, Tumor Proto-Oncogene Proteins c-met genetics Carcinoma, Non-Small-Cell Lung drug therapy Carcinoma, Non-Small-Cell Lung genetics Carcinoma, Non-Small-Cell Lung pathology Lung Neoplasms drug therapy Lung Neoplasms genetics Lung Neoplasms pathology
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [Br J Cancer] 2023 Jun; Vol. 128 (12), pp. 2186-2196. <i>Date of Electronic Publication: </i>2023 Apr 14. MeSH Terms: Carcinoma, Non-Small-Cell Lung* / drug therapy ; Carcinoma, Non-Small-Cell Lung* / genetics ; Carcinoma, Non-Small-Cell Lung* / pathology ; Lung Neoplasms* / drug therapy ; Lung Neoplasms* / genetics ; Lung Neoplasms* / pathology ; Humans ; Drug Resistance, Neoplasm / genetics ; ErbB Receptors / genetics ; ErbB Receptors / metabolism ; Gefitinib ; Protein Kinase Inhibitors / pharmacology ; Protein Kinase Inhibitors / therapeutic use ; Mutation ; Cell Line, Tumor ; Proto-Oncogene Proteins c-met / genetics References: Chan BA, Hughes BG. Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. Transl Lung Cancer Res. 2015;4:36–54. 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Transient IGF-1R inhibition combined with osimertinib eradicates AXL-low expressing EGFR mutated lung cancer. Nat Commun. 2020;11:4607. (PMID: 10.1038/s41467-020-18442-4329290817490421) Substance Nomenclature: EC 2.7.10.1 (ErbB Receptors) ; S65743JHBS (Gefitinib) ; 0 (Protein Kinase Inhibitors) ; EC 2.7.10.1 (Proto-Oncogene Proteins c-met) ; EC 2.7.10.1 (EGFR protein, human) Entry Date(s): Date Created: 20230414 Date Completed: 20230607 Latest Revision: 20240415 Update Code: 20240415 PubMed Central ID: PMC10241937

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Single targeting of MET in EGFR-mutated and MET-amplified non-small cell lung cancer.