Reference Detail

Ref Type

Journal Article

PMID

(27760835)

Authors

Wu M, Huang J, Zhang J, Benes C, Jiao B, Ren R

Title

N-Arachidonoyl Dopamine Inhibits NRAS Neoplastic Transformation by Suppressing Its Plasma Membrane Translocation.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	16	1	2017 Jan	57-67	Mol Cancer Ther

URL

Abstract Text

RAS oncogenic mutations are common in human cancers, but RAS proteins have been difficult to target. We sought to identify pharmacological agents to block RAS oncogenic signaling by a distinct mechanism. Because the biological activity of RAS proteins relies upon lipid modifications and RAS regulates lipid metabolisms in cancer cells, we screened a bioactive lipid library using a RAS-specific cell viability assay. We report the discovery of a new class of inhibitors for RAS transformation. Compounds in the class represented by endocannabinoid N-arachidonoyl dopamine (NADA) can induce cell oncosis, independent of its ability to engage cannabinoid receptors. Further analyses show that NADA is more active in inhibiting the NRAS transformation and signaling than that of KRAS4B. Mechanistically, NADA blocks the plasma membrane translocation of NRAS, but not that of KRAS4B. In addition, NADA inhibits plasma membrane translocation and neoplastic transformation of oncogenic KRAS4A. Interestingly, NADA also redistributes the cytoplasmic NRAS to the Golgi apparatus in a palmitoylation-dependent manner. The results indicate that NADA inhibits NRAS and KRAS4A plasma membrane translocation by targeting a novel molecular process. The new findings would help to develop novel targeted therapies for a broad range of human cancers. Mol Cancer Ther; 16(1); 57-67. ©2016 AACR.

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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
N-Arachidonoyl Dopamine	N-Arachidonoyl Dopamine	1	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
N-Arachidonoyl Dopamine		NADA		N-Arachidonoyl Dopamine (NADA) is an endocannabinoid that inhibits translocation of RAS proteins to the cellular membrane, thereby reducing RAS signaling and potentially inhibiting growth of RAS-dependent tumor cells (PMID: 27760835).

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 G12D	Advanced Solid Tumor	sensitive	N-Arachidonoyl Dopamine	Preclinical - Cell culture	Actionable	In a preclinical study, N-Arachidonoyl Dopamine (NADA) disrupted NRAS protein membrane localization and decreased NRAS downstream signaling, and inhibited proliferation and induced cell death in transformed cells expressing NRAS G12D in culture (PMID: 27760835).	27760835