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2016-12-13

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cc-by (c) Queralt, Bernat et al., 2016
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/178706

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

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Recurs relacionat

https://doi.org/10.18632/oncotarget.11985

Resum

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.

Matèries

Proteïnes quinases, Càncer colorectal, Mutació (Biologia), Farmacologia

Matèries (anglès)

Protein kinases, Colorectal cancer, Mutation (Biology), Pharmacology

Citació

Col·leccions

Articles publicats en revistes (Ciències Clíniques)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

Citació

QUERALT, Bernat, et al. Synthetic lethal interaction of cetuximab with MEK1/2 inhibition in NRAS-mutant metastatic colorectal cancer. Oncotarget. 2016. Vol. 7, num. 50, pags. 82185-82199. ISSN 1949-2553. [consulted: 16 of August of 2026]. Available at: https://hdl.handle.net/2445/178706

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