Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Oncotarget	7	50	2016 Dec 13	82185-82199	Oncotarget

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	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
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
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
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
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