A therapeutic vulnerability linking MNK1/2 inhibition and G1/S cyclin-dependent kinase blockade in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a clinically challenging disease with limited therapeutic options. MAP kinase-interacting kinases 1 and 2 (MNK1/2)-mediated phosphorylation of eukaryotic initiation factor 4E (eIF4E) promotes oncogenic translation and represents a potential therapeutic target. We previously showed that loss of eIF4E phosphorylation suppresses metastasis but not primary tumor growth. Here, an shRNA screen surveying druggable genes unveiled cyclin-dependent kinase 4 (CDK4) as a genetic vulnerability to MNK1/2 inhibition in MDA-MB-231 TNBC cells. Although CDK4/6 inhibitors are approved for hormone receptor (HR)-positive, HER2-negative breast cancer, they are not approved for TNBC. We demonstrate that MNK1/2 inhibition synergizes with CDK4/6 blockade suppresses TNBC cell growth, a synergy also observed in another independent TNBC cell line (SUM159) using a broader G1/S CDK (CDK2/4/6) inhibitor. Integrated RNA sequencing and ribosome profiling revealed combination-specific changes in translation associated with mitotic checkpoint control and DNA repair. Our findings document MNK1/2 inhibition as a strategy to sensitize TNBC to G1/S CDK inhibition and provide a new avenue for therapeutic combination.