ETC-501 Is a Brain-Penetrant MNK Inhibitor That Potentiates TMZ-Induced Senescence and Sensitizes Glioblastoma Cells to Senolytic Therapy

Glioblastoma (GBM) is the deadliest primary brain tumor in adults, with a median survival of only 15 months and fewer than 10% of patients surviving beyond 5 years. Despite aggressive multimodal therapies, including surgical resection, radiation, and temozolomide (TMZ) chemotherapy, recurrence is almost inevitable. The mitogen-activated protein kinase interacting kinases (MNK)-eIF4E axis plays a significant role in cancer cell survival, and MNK1 and MNK2 are upregulated in gliomas. In this study, we discovered that elevated MNK1/2 expression correlates with poor prognosis and aggressive GBM phenotypes. The development of ETC-501, a selective brain-penetrant MNK inhibitor, enabled modulation of key oncogenic pathways, including MYC signaling, DNA replication, cell-cycle regulation, and inflammation. ETC-501 effectively inhibited GBM proliferation, impaired DNA damage repair, delayed cell-cycle progression, and suppressed ribosome biogenesis. Notably, in combination with TMZ, ETC-501 not only enhanced senescence but also attenuated the senescence-associated secretory phenotype in GBM cells. The augmented senescence increased the vulnerability of GBM cells to the senolytic agent navitoclax, facilitating the targeted elimination of residual senescent cells. These findings underscore the therapeutic potential of MNK inhibition in GBM, offering a promising strategy to advance GBM treatment paradigms and improve patient outcomes. SIGNIFICANCE: Targeting MNK1/2 enhances the efficacy of cancer therapy and promotes senescence to prime cancer cells for elimination by senolytic drugs, providing a treatment strategy to manage tumor recurrence in glioblastoma.