Abstract 4726: ETC-501, a novel brain penetrant MNK kinase inhibitor, potentiates TMZ-induced senescence and sensitizes glioblastoma cells to senolytic therapy

Abstract Glioblastoma (GBM), the most lethal primary brain tumor in adults, has a median survival of only 15 months, with fewer than 10% of patients surviving beyond five years. Despite aggressive multimodal therapies, including maximal surgical resection, radiation, and temozolomide (TMZ) chemotherapy, recurrence is almost inevitable. Contributing factors include incomplete resection, elevated levels of O6-methylguanine DNA methyltransferase that repair TMZ-induced DNA damage, therapy-resistant glioma stem cells, intratumoral heterogeneity, and the restrictive blood-brain barrier. Additionally, therapy-induced senescence from chemoradiation poses further challenges, as senescent glioma cells secrete pro-tumorigenic senescence-associated secretory phenotype (SASP) factors and may escape senescence, potentially facilitating recurrence. To evaluate the clinical relevance of MNK kinases in gliomas, we analyzed data from The Cancer Genome Atlas (TCGA), showing that elevated MNK1 and MNK2 expression correlates with increased tumor aggressiveness and poor prognosis. Genetic knockdown experiments confirmed that MNK1/2 are essential for GBM growth in vitro and drive aggressive behavior in vivo. To exploit their therapeutic potential, we developed ETC-501, a potent, selective, brain-penetrant MNK inhibitor. ETC-501 inhibited critical GBM processes, including MYC-driven transcriptional programs, DNA replication, ribosome biogenesis, inflammatory responses, and coagulation. Importantly, in combination with TMZ, ETC-501 significantly enhanced TMZ-induced senescence and reduced tumor-promoting SASP factors in GBM cells, acting both as a senescence inducer and senomorphic. Leveraging this enhanced senescence, we increased the susceptibility of GBM cells to the senolytic agent navitoclax, enabling targeted clearance of residual senescent cells. This “one-two punch” therapeutic strategy effectively eradicated cells that could otherwise act as reservoirs for recurrence. Our findings underscore the therapeutic potential of MNK inhibition in GBM, advancing our approach to managing GBM and potentially other malignancies characterized by senescence and SASP. Citation Format: Giselle Nah, Yuk Kien Chong, Fatin Nasha Sulaimi, Kian Leong Lee, See Wee Lim, Kassoum Nacro, Jeffrey Hill, Alex Matter, Henry Yang, Beng Ti Ang, Carol Tang, Sin Tiong Ong. ETC-501, a novel brain penetrant MNK kinase inhibitor, potentiates TMZ-induced senescence and sensitizes glioblastoma cells to senolytic therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4726.