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Ref Type Journal Article
PMID (27636997)
Authors Queralt B, Cuyàs E, Bosch-Barrera J, Massaguer A, de Llorens R, Martin-Castillo B, Brunet J, Salazar R, Menendez JA
Title Synthetic lethal interaction of cetuximab with MEK1/2 inhibition in NRAS-mutant metastatic colorectal cancer.
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NRAS Q61K colon cancer resistant Cetuximab Preclinical - Cell culture Actionable In a preclinical study, a colon cancer cell line expressing NRAS Q61K was resistant to Erbitux (cetuximab) in culture (PMID: 27636997). 27636997
NRAS Q61K colon cancer sensitive Cetuximab + Pimasertib Preclinical - Cell culture Actionable In a preclinical study, Erbitux (cetuximab) and Pimasertib (MSC19363669B) synergistically induced apoptosis and inhibited proliferation and viability of a colon cancer cell line expressing NRAS Q61K in culture (PMID: 27636997). 27636997
NRAS Q61K colon cancer sensitive Cetuximab + Selumetinib Preclinical - Cell culture Actionable In a preclinical study, Erbitux (cetuximab) and Koselugo (selumetinib) synergistically induced apoptosis and inhibited viability of a colon cancer cell line expressing NRAS Q61K in culture (PMID: 27636997). 27636997
PIK3CA H1047R colon cancer sensitive Pimasertib Preclinical - Cell culture Actionable In a preclinical study, Pimasertib (MSC1936369B) inhibited viability of a colon cancer cell line expressing PIK3CA H1047R in culture (PMID: 27636997). 27636997
PIK3CA H1047R colon cancer sensitive Selumetinib Preclinical - Cell culture Actionable In a preclinical study, Koselugo (selumetinib) inhibited viability of a colon cancer cell line expressing PIK3CA H1047R in culture (PMID: 27636997). 27636997
NRAS Q61K colon cancer sensitive Cetuximab + Trametinib Preclinical - Cell culture Actionable In a preclinical study, Erbitux (cetuximab) and Mekinist (trametinib) synergistically induced apoptosis and inhibited viability of a colon cancer cell line expressing NRAS Q61K in culture (PMID: 27636997). 27636997