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DC Field | Value | Language |
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dc.contributor.author | Queralt, Bernat | - |
dc.contributor.author | Cuyàs, Elisabet | - |
dc.contributor.author | Bosch Barrera, Joaquim | - |
dc.contributor.author | Massaguer i Vall-llovera, Anna | - |
dc.contributor.author | Llorens Duran, Rafael de | - |
dc.contributor.author | Martin Castillo, Begoña | - |
dc.contributor.author | Brunet, Joan | - |
dc.contributor.author | Salazar Soler, Ramón | - |
dc.contributor.author | Menendez, Javier A. | - |
dc.date.accessioned | 2021-06-29T17:03:17Z | - |
dc.date.available | 2021-06-29T17:03:17Z | - |
dc.date.issued | 2016-12-13 | - |
dc.identifier.issn | 1949-2553 | - |
dc.identifier.uri | http://hdl.handle.net/2445/178706 | - |
dc.description.abstract | KRAS mutations are an established predictor of lack of response to EGFR-targeted therapies in patients with metastatic colorectal cancer (mCRC). However, little is known about the role of the rarer NRAS mutations as a mechanism of primary resistance to the anti-EGFR monoclonal antibody cetuximab in wild-type KRAS mCRC. Using isogenic mCRC cells with a heterozygous knock-in of the NRAS activating mutation Q61K, we aimed to elucidate the mechanism(s) by which mutant NRAS blocks cetuximab from inhibiting mCRC growth. NRASQ61K/+ cells were refractory to cetuximab-induced growth inhibition. Pathway-oriented proteome profiling revealed that cetuximab-unresponsive ERK1/2 phosphorylation was the sole biomarker distinguishing cetuximab-refractory NRASQ61K/+ from cetuximab-sensitive NRAS+/+ cells. We therefore employed four representative MEK1/2 inhibitors (binimetinib, trametinib, selumetinib, and pimasertib) to evaluate the therapeutic value of MEK/ERK signaling in cetuximab-refractory NRAS mutation-induced mCRC. Co-treatment with an ineffective dose of cetuximab augmented, up to more than 1,300-fold, the cytotoxic effects of pimasertib against NRASQ61K/+ cells. Simultaneous combination of MEK1/2 inhibitors with cetuximab resulted in extremely high and dose-dependent synthetic lethal effects, which were executed, at least in part, by exacerbated apoptotic cell death. Dynamic monitoring of real-time cell growth rates confirmed that cetuximab synergistically sensitized NRASQ61K/+ cellsto MEK1/2 inhibition. Our discovery of a synthetic lethal interaction of cetuximab in combination with MEK1/2 inhibition for the NRAS mutant subgroup of mCRC underscores the importance of therapeutic intervention both in the MEK-ERK and EGFR pathways to achieve maximal therapeutic efficacy against NRAS-mutant mCRC tumors. | - |
dc.format.extent | 15 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | Impact Journals | - |
dc.relation.isformatof | Reproducció del document publicat a: https://doi.org/10.18632/oncotarget.11985 | - |
dc.relation.ispartof | Oncotarget, 2016, vol. 7, num. 50, p. 82185-82199 | - |
dc.relation.uri | https://doi.org/10.18632/oncotarget.11985 | - |
dc.rights | cc-by (c) Queralt, Bernat et al., 2016 | - |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | - |
dc.source | Articles publicats en revistes (Ciències Clíniques) | - |
dc.subject.classification | Proteïnes quinases | - |
dc.subject.classification | Càncer colorectal | - |
dc.subject.classification | Mutació (Biologia) | - |
dc.subject.classification | Farmacologia | - |
dc.subject.other | Protein kinases | - |
dc.subject.other | Colorectal cancer | - |
dc.subject.other | Mutation (Biology) | - |
dc.subject.other | Pharmacology | - |
dc.title | Synthetic lethal interaction of cetuximab with MEK1/2 inhibition in NRAS-mutant metastatic colorectal cancer | - |
dc.type | info:eu-repo/semantics/article | - |
dc.type | info:eu-repo/semantics/publishedVersion | - |
dc.identifier.idgrec | 664952 | - |
dc.date.updated | 2021-06-29T17:03:17Z | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | - |
dc.identifier.pmid | 27636997 | - |
Appears in Collections: | Articles publicats en revistes (Ciències Clíniques) Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
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664952.pdf | 4.5 MB | Adobe PDF | View/Open |
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