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Pàgina inicial > Articles > Articles publicats > Dual MET and ERBB inhibition overcomes intratumor plasticity in osimertinib-resistant-advanced non-small-cell lung cancer (NSCLC) |
Data: | 2017 |
Resum: | 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. |
Ajuts: | Instituto de Salud Carlos III PI14/01248 Instituto de Salud Carlos III PI13/01339 Instituto de Salud Carlos III PIE13/00022 Instituto de Salud Carlos III PI16/01898 Instituto de Salud Carlos III CPII14/00037 Instituto de Salud Carlos III CP14/00229 |
Nota: | Altres ajuts: ACEE (GCB14-2170); Fundación Mutua Madrileña (AP150932014) |
Drets: | 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. |
Llengua: | Anglès |
Document: | Article ; recerca ; Versió publicada |
Matèria: | NSCLC ; EGFR ; T790M ; MET ; Acquired resistance ; Intratumor plasticity |
Publicat a: | Annals of oncology, Vol. 28 (july 2017) , p. 2451-2457, ISSN 1569-8041 |
7 p, 740.6 KB |