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|Ref Type||Journal Article|
|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||The Journal of clinical investigation|
|Date||2017 Nov 01|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|SEL201||MNK1/2 Inhibitor 3||SEL210 selectively inhibits MNK1 and MNK2, resulting in inhibition of tumor cell growth and metastasis (PMID: 29035277).|
|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 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|
|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||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 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 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|