Synthetic lethal interaction of cetuximab with MEK1/2 inhibition in NRAS-mutant metastatic colorectal cancer

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...

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Autores: Queralt, Bernat, Cuyàs, Elisabet, Bosch Barrera, Joaquim, Massaguer i Vall-llovera, Anna, Llorens Duran, Rafael de, Martin Castillo, Begoña, Brunet, Joan, Salazar Soler, Ramón, Menendez, Javier A.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2016
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/178706
Acceso en línea:https://hdl.handle.net/2445/178706
Access Level:acceso abierto
Palabra clave:Proteïnes quinases
Càncer colorectal
Mutació (Biologia)
Farmacologia
Protein kinases
Colorectal cancer
Mutation (Biology)
Pharmacology
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spelling Synthetic lethal interaction of cetuximab with MEK1/2 inhibition in NRAS-mutant metastatic colorectal cancerQueralt, BernatCuyàs, ElisabetBosch Barrera, JoaquimMassaguer i Vall-llovera, AnnaLlorens Duran, Rafael deMartin Castillo, BegoñaBrunet, JoanSalazar Soler, RamónMenendez, Javier A.Proteïnes quinasesCàncer colorectalMutació (Biologia)FarmacologiaProtein kinasesColorectal cancerMutation (Biology)PharmacologyKRAS 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.Impact Journals2016info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/178706Articles publicats en revistes (Ciències Clíniques)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.18632/oncotarget.11985Oncotarget, 2016, vol. 7, num. 50, p. 82185-82199https://doi.org/10.18632/oncotarget.11985cc-by (c) Queralt, Bernat et al., 2016https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1787062026-05-27T06:46:51Z
dc.title.none.fl_str_mv Synthetic lethal interaction of cetuximab with MEK1/2 inhibition in NRAS-mutant metastatic colorectal cancer
title Synthetic lethal interaction of cetuximab with MEK1/2 inhibition in NRAS-mutant metastatic colorectal cancer
spellingShingle Synthetic lethal interaction of cetuximab with MEK1/2 inhibition in NRAS-mutant metastatic colorectal cancer
Queralt, Bernat
Proteïnes quinases
Càncer colorectal
Mutació (Biologia)
Farmacologia
Protein kinases
Colorectal cancer
Mutation (Biology)
Pharmacology
title_short Synthetic lethal interaction of cetuximab with MEK1/2 inhibition in NRAS-mutant metastatic colorectal cancer
title_full Synthetic lethal interaction of cetuximab with MEK1/2 inhibition in NRAS-mutant metastatic colorectal cancer
title_fullStr Synthetic lethal interaction of cetuximab with MEK1/2 inhibition in NRAS-mutant metastatic colorectal cancer
title_full_unstemmed Synthetic lethal interaction of cetuximab with MEK1/2 inhibition in NRAS-mutant metastatic colorectal cancer
title_sort Synthetic lethal interaction of cetuximab with MEK1/2 inhibition in NRAS-mutant metastatic colorectal cancer
dc.creator.none.fl_str_mv Queralt, Bernat
Cuyàs, Elisabet
Bosch Barrera, Joaquim
Massaguer i Vall-llovera, Anna
Llorens Duran, Rafael de
Martin Castillo, Begoña
Brunet, Joan
Salazar Soler, Ramón
Menendez, Javier A.
author Queralt, Bernat
author_facet Queralt, Bernat
Cuyàs, Elisabet
Bosch Barrera, Joaquim
Massaguer i Vall-llovera, Anna
Llorens Duran, Rafael de
Martin Castillo, Begoña
Brunet, Joan
Salazar Soler, Ramón
Menendez, Javier A.
author_role author
author2 Cuyàs, Elisabet
Bosch Barrera, Joaquim
Massaguer i Vall-llovera, Anna
Llorens Duran, Rafael de
Martin Castillo, Begoña
Brunet, Joan
Salazar Soler, Ramón
Menendez, Javier A.
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Proteïnes quinases
Càncer colorectal
Mutació (Biologia)
Farmacologia
Protein kinases
Colorectal cancer
Mutation (Biology)
Pharmacology
topic Proteïnes quinases
Càncer colorectal
Mutació (Biologia)
Farmacologia
Protein kinases
Colorectal cancer
Mutation (Biology)
Pharmacology
description 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.
publishDate 2016
dc.date.none.fl_str_mv 2016
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/178706
url https://hdl.handle.net/2445/178706
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.18632/oncotarget.11985
Oncotarget, 2016, vol. 7, num. 50, p. 82185-82199
https://doi.org/10.18632/oncotarget.11985
dc.rights.none.fl_str_mv cc-by (c) Queralt, Bernat et al., 2016
https://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Queralt, Bernat et al., 2016
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Impact Journals
publisher.none.fl_str_mv Impact Journals
dc.source.none.fl_str_mv Articles publicats en revistes (Ciències Clíniques)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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