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|Ref Type||Journal Article|
|Authors||Kumar K, Chow CR, Ebine K, Arslan AD, Kwok B, Bentrem DJ, Eckerdt FD, Platanias LC, Munshi HG|
|Title||Differential Regulation of ZEB1 and EMT by MAPK-Interacting Protein Kinases (MNK) and eIF4E in Pancreatic Cancer.|
|Journal||Molecular cancer research : MCR|
|Abstract Text||Human pancreatic ductal adenocarcinoma (PDAC) tumors are associated with dysregulation of mRNA translation. In this report, it is demonstrated that PDAC cells grown in collagen exhibit increased activation of the MAPK-interacting protein kinases (MNK) that mediate eIF4E phosphorylation. Pharmacologic and genetic targeting of MNKs reverse epithelial-mesenchymal transition (EMT), decrease cell migration, and reduce protein expression of the EMT-regulator ZEB1 without affecting ZEB1 mRNA levels. Paradoxically, targeting eIF4E, the best-characterized effector of MNKs, increases ZEB1 mRNA expression through repression of ZEB1-targeting miRNAs, miR-200c and miR-141. In contrast, targeting the MNK effector hnRNPA1, which can function as a translational repressor, increases ZEB1 protein without increasing ZEB1 mRNA levels. Importantly, treatment with MNK inhibitors blocks growth of chemoresistant PDAC cells in collagen and decreases the number of aldehyde dehydrogenase activity-positive (Aldefluor+) cells. Significantly, MNK inhibitors increase E-cadherin mRNA levels and decrease vimentin mRNA levels in human PDAC organoids without affecting ZEB1 mRNA levels. Importantly, MNK inhibitors also decrease growth of human PDAC organoids.These results demonstrate differential regulation of ZEB1 and EMT by MNKs and eIF4E, and identify MNKs as potential targets in pancreatic cancer.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|CGP57380||CGP-57380|CGP 57380||MNK1/2 Inhibitor 3||CGP57380 inhibits MAPK-interacting protein kinase (MNK) 1 and 2, and may have additional activity against other protein kinases, leading to decreased phosphorylation of eIF4E and potentially resulting in decreased tumor cell growth and migration (PMID: 17850214, PMID: 21406405, PMID: 26609108, PMID: 30297804).|
|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|
|Unknown unknown||pancreatic adenocarcinoma||not applicable||CGP57380||Preclinical||Actionable||In a preclinical study, CGP57380 decreased migration of pancreatic adenocarcinoma (PDAC) cells in culture and inhibited growth of organoids generated from human PDAC samples (PMID: 26609108).||26609108|