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dc.contributorVall d'Hebron Barcelona Hospital Campus
dc.contributor.authorNapolitano, Stefania
dc.contributor.authorMatrone, Nunzia
dc.contributor.authorMuddassir, A. L.
dc.contributor.authorMartini, Giulia
dc.contributor.authorSorokin, A.
dc.contributor.authorDe Falco, Vincenzo
dc.date.accessioned2021-04-20T09:42:10Z
dc.date.available2021-04-20T09:42:10Z
dc.date.issued2019-12-16
dc.identifier.citationNapolitano S, Matrone N, Muddassir AL, Martini G, Sorokin A, De Falco V, et al. Triple blockade of EGFR, MEK and PD-L1 has antitumor activity in colorectal cancer models with constitutive activation of MAPK signaling and PD-L1 overexpression. J Exp Clin Cancer Res. 2019 Dec 16;38(1):492.
dc.identifier.issn1756-9966
dc.identifier.urihttp://hdl.handle.net/11351/5877
dc.descriptionColorectal cancer; MEK inhibitor resistance; PD-L1 inhibitors
dc.description.abstractBackground Molecular mechanisms driving acquired resistance to anti-EGFR therapies in metastatic colorectal cancer (mCRC) are complex but generally involve the activation of the downstream RAS-RAF-MEK-MAPK pathway. Nevertheless, even if inhibition of EGFR and MEK could be a strategy for overcoming anti-EGFR resistance, its use is limited by the development of MEK inhibitor (MEKi) resistance. Methods We have generated in vitro and in vivo different CRC models in order to underline the mechanisms of MEKi resistance. Results The three different in vitro MEKi resistant models, two generated by human CRC cells quadruple wild type for KRAS, NRAS, BRAF, PI3KCA genes (SW48-MR and LIM1215-MR) and one by human CRC cells harboring KRAS mutation (HCT116-MR) showed features related to the gene signature of colorectal cancer CMS4 with up-regulation of immune pathway as confirmed by microarray and western blot analysis. In particular, the MEKi phenotype was associated with the loss of epithelial features and acquisition of mesenchymal markers and morphology. The change in morphology was accompanied by up-regulation of PD-L1 expression and activation of EGFR and its downstream pathway, independently to RAS mutation status. To extend these in vitro findings, we have obtained mouse colon cancer MC38- and CT26-MEKi resistant syngeneic models (MC38-MR and CT26-MR). Combined treatment with MEKi, EGFR inhibitor (EGFRi) and PD-L1 inhibitor (PD-L1i) resulted in a marked inhibition of tumor growth in both models. Conclusions These results suggest a strategy to potentially improve the efficacy of MEK inhibition by co-treatment with EGFR and PD-L1 inhibitors via modulation of host immune responses.
dc.language.isoeng
dc.publisherBMC
dc.relation.ispartofseriesJournal of Experimental & Clinical Cancer Research;38(1)
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceScientia
dc.subjectRecte - Càncer
dc.subjectCòlon - Càncer
dc.subjectResistència als medicaments
dc.subject.meshColorectal Neoplasms
dc.subject.mesh/genetics
dc.subject.meshDrug Resistance, Neoplasm
dc.titleTriple blockade of EGFR, MEK and PD-L1 has antitumor activity in colorectal cancer models with constitutive activation of MAPK signaling and PD-L1 overexpression
dc.typeinfo:eu-repo/semantics/article
dc.identifier.doi10.1186/s13046-019-1497-0
dc.subject.decsneoplasias colorrectales
dc.subject.decs/genética
dc.subject.decsresistencia a los antineoplásicos
dc.relation.publishversionhttps://jeccr.biomedcentral.com/articles/10.1186/s13046-019-1497-0
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dc.audienceProfessionals
dc.contributor.organismesInstitut Català de la Salut
dc.contributor.authoraffiliation[Napolitano S] Medical Oncology Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80100 Naples, Italy. Department of Gastrointestinal Medical Oncology, Division of Cancer Medicin0065, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. [Matrone N] Medical Oncology Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80100 Naples, Italy. Medical University of Vienna, Institute for Cancer Research, Borschkegasse 8A, 1090 Wien, Austria. [Muddassir AL, Sorokin A] Department of Gastrointestinal Medical Oncology, Division of Cancer Medicin0065, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. [Martini G] Medical Oncology Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80100 Naples, Italy. Gastrointestinal and neuroendocrine tumor group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [De Falco V] Medical Oncology Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80100 Naples, Italy
dc.identifier.pmid31842958
dc.identifier.wos000510641700001
dc.rights.accessrightsinfo:eu-repo/semantics/openAccess


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