dc.contributor.author |
Queralt, Bernardo |
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 i Vidal, Joan |
dc.contributor.author |
Salazar, Ramon |
dc.contributor.author |
Menéndez Menéndez, Javier Abel |
dc.date |
2017-05-19T08:03:51Z |
dc.date |
2017-05-19T08:03:51Z |
dc.date |
2016-09-12 |
dc.identifier.citation |
1949-2553 |
dc.identifier.uri |
http://hdl.handle.net/10256/14007 |
dc.format |
application/pdf |
dc.language.iso |
eng |
dc.publisher |
Impact Journals |
dc.relation |
http://dx.doi.org/10.18632/oncotarget.11985 |
dc.relation |
Reproducció digital del document publicat a: http://dx.doi.org/10.18632/oncotarget.11985 |
dc.relation |
Oncotarget, 2016, vol. 7, núm. 50, p. 82185-82199 |
dc.relation |
Articles publicats (D-CM) |
dc.rights |
Attribution 3.0 Spain |
dc.rights |
info:eu-repo/semantics/openAccess |
dc.rights |
http://creativecommons.org/licenses/by/3.0/es/ |
dc.subject |
Recte -- Càncer |
dc.subject |
Rectum -- Cancer |
dc.subject |
Càncer -- Tractament |
dc.subject |
Cancer -- Treatment |
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.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 |