Targeting Mnks for Cancer Therapy

Abstract

Deregulation of protein synthesis is a common event in human cancer and a key player in translational control is eIF4E. Elevated expression levels of eIF4E promote cancer development and progression. Recent findings suggest that eIF4E activity is a key determinant of the PI3K/Akt/mTOR and Ras/Raf/MEK/ERK mediated tumorigenic activity and targeting eIF4E should have a major impact on these pathways in human cancer. The function of eIF4E is modulated through phosphorylation of a conserved serine (Ser209) by Mnk1 and Mnk2 downstream of ERK. While the phosphorylation event is necessary for oncogenic transformation, it seems to be dispensable for normal development. Hence, pharmacologic Mnk inhibitors may provide non-toxic and effective anti-cancer strategy. Strong circumstantial evidence indicates that Mnk inhibition presents attractive therapeutic potential, but the lack of selective Mnk inhibitors has so far confounded pharmacological target validation and clinical development.

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

“…Polysome profiling curves of both MNK1/2-knockdown and control groups overlap, consistent with phorylation is required for tumorigenesis, lymphomagenesis, and tumor metastasis, thus making MNK1/2 kinases attractive therapeutic targets (15)(16)(17)(18)(19). As phospho-eIF4E is the convergence point of the RAS/MAPK and PI3K/AKT/mTOR cascades (20), these data provide support for the prospect of targeting MNK1/2 therapeutically in melanomas harboring KIT mutations and amplifications. We therefore sought to determine the effect of pharmacologically and genetically abrogating MNK1/2 activity in KIT-mutant melanomas.…”

Adaptation to mTOR kinase inhibitors by amplification of eIF4E to maintain cap-dependent translation

“…This highlights the importance of eIF4E and its targets as key regulators of cell proliferation downstream of mTOR. Furthermore, increased expression of eIF4E can drive resistance to MEK1/2 inhibitors as well as mTOR kinase inhibitors, consistent with the convergence of both signalling pathways at the level of eIF4E (Hou et al, 2012). This suggests that although mTOR inhibitors and MEK inhibitors can combine well as a primary treatment (Holt et al, 2012), combination with MEK inhibitors might not be fruitful in seeking to overcome acquired resistance to mTOR inhibitors driven by eIF4E amplification.…”

“…In addition, the transforming effects of eIF4E are enhanced by phosphorylation of Ser209, which is catalyzed by the MNK1 and MNK2 protein kinases (Topisirovic et al, 2004;Furic et al, 2010;Ueda et al, 2010). MNK1 and MNK2 are in turn activated by phosphorylation catalyzed by either ERK1/2 or the p38 stress kinases (Waskiewicz et al, 1997;Hou et al, 2012). Given that SW620 cells harbour a KRAS mutation and are strongly dependent on RAF-MEK1/2-ERK1/2 signalling for proliferation we anticipated that a MEK1/2 inhibitor might overcome eIF4E-driven acquired resistance to AZD8055.…”

Inhibition of Tumor Growth and Metastasis in Non–Small Cell Lung Cancer by LY2801653, an Inhibitor of Several Oncokinases, Including MET

“…These in vivo activities of LY2801653 may not be entirely due to the inhibition of MET kinase activity as the kinase selectivity profile of LY2801653 includes other kinases such as MST1R, FLT3, AXL, MER, TEK, ROS1, DDR1/2, and MKNK1/2 (13). The reduction of p-EIF4E (a substrate of MKNK1/2) in the H441 tumor tissues treated by LY2801653 may be a contribution from inhibition of both MET and MKNK1/2 (40)(41)(42). On the other hand, H1299 cells express high level of AXL, a receptor tyrosine oncokinase, and LY2801653 was shown to inhibit AXL with an IC 50 of 2 nmol/L (13).…”