Repurposing Entrectinib and Ibrutinib as MNK/eIF4E Pathway Modulators in Ovarian Cancer.

Abstract

The ERK/MNK/eIF4E signaling axis is critically involved in cap-dependent translation and significantly impacts survival and chemotherapy resistance in ovarian cancer. Clinical data indicate that elevated eIF4E expression is an independent prognostic marker for poor overall survival (HR=1.17, p=0.027). However, there has yet to be a systematic evaluation of FDA-approved agents for their efficacy as MNK/eIF4E inhibitors. In the present study, a total of 2,180 FDA-approved compounds were screened using a comprehensive approach integrating machine learning, molecular docking, molecular dynamics, and binding free energy analysis to identify potential MNK1 modulators. Ibrutinib and Entrectinib emerged as the most promising candidates, forming stable complexes with MNK1 and displaying favorable binding energies (Entrectinib: ΔG = -131.66 ± 2.05 kJ/mol; Ibrutinib: ΔG = -87.36 ± 2.04 kJ/mol). Notably, Ibrutinib, conventionally recognized as a BTK inhibitor, and Entrectinib, a tropomyosin receptor kinase inhibitor, exhibited previously unreported off-target interactions with MNK1/eIF4E, suggesting new therapeutic applications for both agents. In vitro validation was conducted using the A2780-s and A2780-cp cell lines, with A2780-cp selected for its elevated MNK/eIF4E activity. Niclosamide, identified as an MNK/eIF4E inhibitor, served as a positive control in this investigation. Both compounds significantly diminished cell viability, lowered the p-eIF4E/eIF4E ratio as determined via Western blot analysis, impaired clonogenic survival, and induced S-phase arrest in A2780-cp cells. This study represents the first examination of the roles of Entrectinib and Ibrutinib as modulators of MNK1/eIF4E in ovarian cancer, providing substantial functional evidence for their efficacy in modulating the MNK/eIF4E pathway with eIF4E Phosphorylation-Suppressing Activity.