Oncotarget

Research Papers:

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

Bernardo Queralt, Elisabet Cuyàs, Joaquim Bosch-Barrera, Anna Massaguer, Rafael de Llorens, Begoña Martin-Castillo, Joan Brunet, Ramon Salazar and Javier A. Menendez _

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Oncotarget. 2016; 7:82185-82199. https://doi.org/10.18632/oncotarget.11985

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Abstract

Bernardo Queralt1,2,3,*, Elisabet Cuyàs2,4,*, Joaquim Bosch-Barrera1,2, Anna Massaguer5, Rafael de Llorens5, Begoña Martin-Castillo2,6, Joan Brunet1,2,3, Ramon Salazar7 and Javier A. Menendez2,4

1 Department of Medical Oncology, Catalan Institute of Oncology, Girona, Catalonia, Spain

2 Girona Biomedical Research Institute, Girona, Catalonia, Spain

3 Department of Medical Sciences, Medical School, University of Girona, Girona, Spain

4 ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism & Cancer Group, Catalan Institute of Oncology, Girona, Catalonia, Spain

5 Biochemistry and Molecular Biology Unit, Department of Biology, University of Girona, Girona, Spain

6 Unit of Clinical Research, Catalan Institute of Oncology, Girona, Catalonia, Spain

7 Department of Medical Oncology, Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, L’Hospitalet de Llobregat, Barcelona, Spain

* These authors have contributed equally to this work

Correspondence to:

Javier A. Menendez, email:

Keywords: colon cancer, KRAS, NRAS, cetuximab, MEK1/2

Received: July 25, 2016 Accepted: September 09, 2016 Published: December 13, 2016

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.


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