Web of Science: 10 citations, Scopus: 12 citations, Google Scholar: citations,
Dual MET and ERBB inhibition overcomes intratumor plasticity in osimertinib-resistant-advanced non-small-cell lung cancer (NSCLC)
Martinez-Marti, Alex (Universitat Autònoma de Barcelona)
Felip Font, Enriqueta (Universitat Autònoma de Barcelona)
Matito, J (Institut d'Oncologia de la Vall d'Hebron)
Mereu, Elisabetta (Universitat Pompeu Fabra)
Navarro, A (Vall d'Hebron Institut d'Oncologia)
Cedrés, S (Vall d'Hebron Institut d'Oncologia)
Pardo Aranda, Núria (Universitat Autònoma de Barcelona)
Martinez de Castro, A (Vall d'Hebron Institut d'Oncologia)
Remon, J (Vall d'Hebron Institut d'Oncologia)
Miquel, J M (Vall d'Hebron Institut d'Oncologia)
Guillaumet-Adkins, A (Universitat Pompeu Fabra)
Nadal, E (Institut Català d'Oncologia)
Rodriguez Esteban, Gustavo (Universitat Pompeu Fabra)
Arqués, O (Stem Cells and Cancer Group)
Fasani, R (Vall d'Hebron Institut d'Oncologia)
Nuciforo, P (Vall d'Hebron Institut d'Oncologia)
Heyn, Holger (Universitat Pompeu Fabra)
Villanueva, A (Institut Català d'Oncologia)
Palmer, H G (Stem Cells and Cancer Group)
Vivancos, A (Vall d'Hebron Institut d'Oncologia)

Date: 2017
Abstract: Third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as osimertinib are the last line of targeted treatment of metastatic non-small-cell lung cancer (NSCLC) EGFR -mutant harboring T790M. Different mechanisms of acquired resistance to third-generation EGFR-TKIs have been proposed. It is therefore crucial to identify new and effective strategies to overcome successive acquired mechanisms of resistance. For Amplicon-seq analysis, samples from the index patient (primary and metastasis lesions at different timepoints) as well as the patient-derived orthotopic xenograft tumors corresponding to the different treatment arms were used. All samples were formalin-fixed paraffin-embedded, selected and evaluated by a pathologist. For droplet digital PCR, 20 patients diagnosed with NSCLC at baseline or progression to different lines of TKI therapies were selected. Formalin-fixed paraffin-embedded blocks corresponding to either primary tumor or metastasis specimens were used for analysis. For single-cell analysis, orthotopically grown metastases were dissected from the brain of an athymic nu/nu mouse and cryopreserved at −80°C. In a brain metastasis lesion from a NSCLC patient presenting an EGFR T790M mutation, we detected MET gene amplification after prolonged treatment with osimertinib. Importantly, the combination of capmatinib (c-MET inhibitor) and afatinib (ErbB-1/2/4 inhibitor) completely suppressed tumor growth in mice orthotopically injected with cells derived from this brain metastasis. In those mice treated with capmatinib or afatinib as monotherapy, we observed the emergence of KRAS G12C clones. Single-cell gene expression analyses also revealed intratumor heterogeneity, indicating the presence of a KRAS -driven subclone. We also detected low-frequent KRAS G12C alleles in patients treated with various EGFR-TKIs. Acquired resistance to subsequent EGFR-TKI treatment lines in EGFR -mutant lung cancer patients may induce genetic plasticity. We assess the biological insights of tumor heterogeneity in an osimertinib-resistant tumor with acquired MET- amplification and propose new treatment strategies in this situation.
Note: Número d'acord de subvenció FIS/PI14/01248
Note: Número d'acord de subvenció FIS/PI13/01339
Note: Número d'acord de subvenció FIS/PIE13/00022
Note: Número d'acord de subvenció FIS/PI16/01898
Note: Número d'acord de subvenció ISCIII/CPII14/00037
Note: Número d'acord de subvenció ISCIII/CP14/00229
Note: Altres ajuts: ACEE (GCB14-2170); Fundación Mutua Madrileña (AP150932014)
Rights: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. Creative Commons
Language: Anglès.
Document: article ; publishedVersion
Subject: NSCLC ; EGFR ; T790M ; MET ; Acquired resistance ; Intratumor plasticity
Published in: Annals of Oncology, Vol. 28 (july 2017) , p. 2451-2457, ISSN 1569-8041

PMID: 28961841
DOI: 10.1093/annonc/mdx396


7 p, 740.6 KB

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Articles > Published articles

 Record created 2018-12-31, last modified 2019-02-18



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