Reference Detail

Ref Type

Journal Article

PMID

(29035277)

Authors

Zhan Y, Guo J, Yang W, Goncalves C, Rzymski T, Dreas A, Żyłkiewicz E, Mikulski M, Brzózka K, Golas A, Kong Y, Ma M, Huang F, Huor B, Guo Q, da Silva SD, Torres J, Cai Y, Topisirovic I, Su J, Bijian K, Alaoui-Jamali MA, Huang S, Journe F, Ghanem GE, Miller WH, Del Rincón SV

Title

MNK1/2 inhibition limits oncogenicity and metastasis of KIT-mutant melanoma.

Journal	Vol	Issue	Date	Pages	Journal Short Title
The Journal of clinical investigation	127	11	2017 Nov 01	4179-4192	J Clin Invest

URL

Abstract Text

Melanoma can be stratified into unique subtypes based on distinct pathologies. The acral/mucosal melanoma subtype is characterized by aberrant and constitutive activation of the proto-oncogene receptor tyrosine kinase C-KIT, which drives tumorigenesis. Treatment of these melanoma patients with C-KIT inhibitors has proven challenging, prompting us to investigate the downstream effectors of the C-KIT receptor. We determined that C-KIT stimulates MAP kinase-interacting serine/threonine kinases 1 and 2 (MNK1/2), which phosphorylate eukaryotic translation initiation factor 4E (eIF4E) and render it oncogenic. Depletion of MNK1/2 in melanoma cells with oncogenic C-KIT inhibited cell migration and mRNA translation of the transcriptional repressor SNAI1 and the cell cycle gene CCNE1. This suggested that blocking MNK1/2 activity may inhibit tumor progression, at least in part, by blocking translation initiation of mRNAs encoding cell migration proteins. Moreover, we developed an MNK1/2 inhibitor (SEL201), and found that SEL201-treated KIT-mutant melanoma cells had lower oncogenicity and reduced metastatic ability. Clinically, tumors from melanoma patients harboring KIT mutations displayed a marked increase in MNK1 and phospho-eIF4E. Thus, our studies indicate that blocking MNK1/2 exerts potent antimelanoma effects and support blocking MNK1/2 as a potential strategy to treat patients positive for KIT mutations.

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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
SEL201	SEL201	2	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
SEL201			MNK1/2 Inhibitor 3	SEL201 selectively inhibits MNK1 and MNK2, resulting in inhibition of tumor cell growth and metastasis (PMID: 29035277, PMID: 31903169).

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
KIT L576P	melanoma	sensitive	Dasatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Sprycel (dasatinib) inhibited MNK pathway activation and proliferation of melanoma cell lines harboring KIT L576P in culture (PMID: 29035277).	29035277
KIT D820Y	melanoma	sensitive	Dasatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Sprycel (dasatinib) inhibited MNK pathway activation and proliferation of melanoma cell lines harboring KIT D820Y in culture (PMID: 29035277).	29035277
KIT D820Y	melanoma	resistant	Imatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Gleevec (imatinib mesylate) failed to inhibit MNK pathway activation and proliferation of melanoma cell lines harboring KIT D820Y in culture (PMID: 29035277).	29035277
KIT L576P	melanoma	sensitive	SEL201	Preclinical - Cell line xenograft	Actionable	In a preclinical study, SEL201 inhibited MNK pathway signaling and growth of melanoma cells harboring KIT L576P in culture, and suppressed tumor metastasis in xenograft models (PMID: 29035277).	29035277
KIT D820Y	melanoma	sensitive	SEL201	Preclinical - Cell line xenograft	Actionable	In a preclinical study, SEL201 inhibited MNK pathway signaling and growth of melanoma cell lines harboring KIT D820Y in culture, and suppressed tumor metastasis in xenograft models (PMID: 29035277).	29035277