title: Therapeutic inhibition of MAP kinase interacting kinase blocks eukaryotic initiation factor 4E phosphorylation and suppresses outgrowth of experimental lung metastases.
abstract: Activation of the translation initiation factor 4E (eIF4E) promotes malignant transformation and metastasis. Signaling through the AKT-mTOR pathway activates eIF4E by phosphorylating the inhibitory 4E binding proteins (4E-BP). This liberates eIF4E and allows binding to eIF4G. eIF4E can then be phosphorylated at serine 209 by the MAPK-interacting kinases (Mnk), which also interact with eIF4G. Although dispensable for normal development, Mnk function and eIF4E phosphorylation promote cellular proliferation and survival and are critical for malignant transformation. Accordingly, Mnk inhibition may serve as an attractive cancer therapy. We now report the identification of a potent, selective and orally bioavailable Mnk inhibitor that effectively blocks 4E phosphorylation both in vitro and in vivo. In cultured cancer cell lines, Mnk inhibitor treatment induces apoptosis and suppresses proliferation and soft agar colonization. Importantly, a single, orally administered dose of this Mnk inhibitor substantially suppresses eIF4E phosphorylation for at least 4 hours in human xenograft tumor tissue and mouse liver tissue. Moreover, oral dosing with the Mnk inhibitor significantly suppresses outgrowth of experimental B16 melanoma pulmonary metastases as well as growth of subcutaneous HCT116 colon carcinoma xenograft tumors, without affecting body weight. These findings offer the first description of a novel, orally bioavailable MNK inhibitor and the first preclinical proof-of-concept that MNK inhibition may provide a tractable cancer therapeutic approach.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Konicek
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Stephens
authors.forename: Ann M
authors.initials: AM
authors.lastname: McNulty
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Robichaud
authors.forename: Robert B
authors.initials: RB
authors.lastname: Peery
authors.forename: Chad A
authors.initials: CA
authors.lastname: Dumstorf
authors.forename: Michele S
authors.initials: MS
authors.lastname: Dowless
authors.forename: Philip W
authors.initials: PW
authors.lastname: Iversen
authors.forename: Stephen
authors.initials: S
authors.lastname: Parsons
authors.forename: Karen E
authors.initials: KE
authors.lastname: Ellis
authors.forename: Denis J
authors.initials: DJ
authors.lastname: McCann
authors.forename: Jerry
authors.initials: J
authors.lastname: Pelletier
authors.forename: Luc
authors.initials: L
authors.lastname: Furic
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Yingling
authors.forename: Louis F
authors.initials: LF
authors.lastname: Stancato
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Graff
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D001572:Benzofurans / Q000494:pharmacology*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis / Q000188:drug therapy; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001572:Benzofurans; D039561:Eukaryotic Initiation Factor-4E; D047908:Intracellular Signaling Peptides and Proteins; C085452:cercosporamide; C491395:MKNK1 protein, human; D017346:Protein Serine-Threonine Kinases