Dual MET and ERBB inhibition overcomes intratumor plasticity in osimertinib-resistant-advanced non-small-cell lung cancer (NSCLC)

Martinez-Marti, Alex; Felip, Enriqueta; Matito, Judit; Mereu, Elisabetta; Navarro, Alejandro; Cedrés, Susana; Pardo, Núria; Martines de Castro, Ana; Remon, Jordi; Miquel, Josep M.; Guillaumet-Adkins, Amy; Nadal, Ernest; Rodríguez Esteban, Gustavo; Arqués, Oriol; Fasani, Roberta; Nuciforo, Paolo G.; Heyn, Holger; Villanueva, Alberto; Palmer, Héctor G.; Vivancos Prellezo, Ana

Dual MET and ERBB inhibition overcomes intratumor plasticity in osimertinib-resistant-advanced non-small-cell lung cancer (NSCLC)

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dc.contributor.author Martinez-Marti, Alexca
dc.contributor.author Felip, Enriquetaca
dc.contributor.author Matito, Juditca
dc.contributor.author Mereu, Elisabettaca
dc.contributor.author Navarro, Alejandroca
dc.contributor.author Cedrés, Susanaca
dc.contributor.author Pardo, Núriaca
dc.contributor.author Martines de Castro, Anaca
dc.contributor.author Remon, Jordica
dc.contributor.author Miquel, Josep M.ca
dc.contributor.author Guillaumet-Adkins, Amyca
dc.contributor.author Nadal, Ernestca
dc.contributor.author Rodríguez Esteban, Gustavoca
dc.contributor.author Arqués, Oriolca
dc.contributor.author Fasani, Robertaca
dc.contributor.author Nuciforo, Paolo G.ca
dc.contributor.author Heyn, Holgerca
dc.contributor.author Villanueva, Albertoca
dc.contributor.author Palmer, Héctor G.ca
dc.contributor.author Vivancos Prellezo, Anaca
dc.date.accessioned 2018-08-21T06:18:07Z
dc.date.available 2018-08-21T06:18:07Z
dc.date.issued 2017
dc.description.abstract BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
dc.description.sponsorship This work was supported by the Spanish Ministries of Health and Fondo de Investigación Sanitaria-Fondo Europeo de Desarrollo Regional (FEDER) (PI14/01248, PI13-01339, PIE13/00022, PI16/01898); AECC Scientific Foundation (GCB14-2170); and Fundación Mutua Madrileña (AP150932014). HGP and HH are Miguel Servet researchers funded by the Spanish Institute of Health Carlos III (CPII14/00037, CP14/00229). PN laboratory is funded by the Tumor Biomarker Research Program of the Banco Bilbao Vizcaya Argentaria Foundation (FBBVA)
dc.format.mimetype application/pdf
dc.identifier.citation Martinez-Marti A, Felip E, Matito J, Mereu E, Navarro A, Cedrés S et al. Dual MET and ERBB inhibition overcomes intratumor plasticity in osimertinib-resistant-advanced non-small-cell lung cancer (NSCLC). Ann Oncol. 2017 Oct 1;28(10):2451-7. DOI: 10.1093/annonc/mdx396
dc.identifier.doi http://dx.doi.org/10.1093/annonc/mdx396
dc.identifier.issn 0923-7534
dc.identifier.uri http://hdl.handle.net/10230/35340
dc.language.iso eng
dc.publisher Oxford University Pressca
dc.relation.ispartof Annals of Oncology. 2017 Oct 1;28(10):2451-7
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by-nc/4.0/
dc.subject.other Immunitat natural
dc.subject.other Pulmons -- Càncer
dc.subject.other Cervell -- Tumors
dc.subject.other Genètica
dc.title Dual MET and ERBB inhibition overcomes intratumor plasticity in osimertinib-resistant-advanced non-small-cell lung cancer (NSCLC)ca
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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