Abstract 6498: MEK inhibitor mirdametinib suppresses MAP kinase pathway activity and inhibits tumor growth in atypical teratoid/rhabdoid tumors

Abstract

Abstract Atypical teratoid/rhabdoid tumors (AT/RT) are deadly infantile brain tumors currently lacking effective treatments. Our prior studies examining AT/RT primary tissues have shown an elevated expression of phospho-ERK, a downstream effector of MEK in the mitogen-activated protein (MAP) kinase pathway. The increased activity of this pathway potentially leads to more aggressive cancer growth, emergence of drug resistance, and poor treatment outcomes in AT/RT patients. Mirdametinib is a novel, highly specific MEK1/2 inhibitor that has been reported to have superior blood-brain-barrier penetration compared to other MEK inhibitors. It is currently in development as a monotherapy for low-grade glioma as well as NF1-related plexiform neurofibromas. We hypothesized that mirdametinib can inhibit AT/RT tumor growth and improve overall survival. We examined the in vitro effect of mirdametinib treatment on five AT/RT cell lines (CHLA04, CHLA05, CHLA06, CHLA266, and BT37). Mirdametinib decreased MAP kinase pathway activity in the tested cell lines (western blot, phospho-ERK). Cell lines treated with mirdametinib exhibited decreased viability at 72hr (Muse Cell Viability Assay, CHLA05 t-test p=0.011, CHLA06 t-test p<0.001, BT37 t-test p<0.01 compared to DMSO control) and lower rates of proliferation (western blot, phospho-RB; BrdU immunofluorescence staining, CHLA05 t-test p=0.015, CHLA06 t-test p<0.0001, BT37 t-test p<0.0001 compared to DMSO control). Furthermore, mirdametinib induced apoptosis in AT/RT cells (western blot, cPARP; Muse Annexin V Assay, CHLA04, CHLA05, CHLA06, and BT37, t-test p<0.0001, CHLA266, t-test p<0.01 compared to DMSO control; cleaved caspase-3 immunofluorescence staining, CHLA05, CHLA06, and BT37, t-test p<0.0001 compared to DMSO control). We then tested the efficacy of mirdametinib in vivo. We treated mice bearing orthotopic CHLA06 tumors with a daily oral delivery of the drug. Mirdametinib treatment significantly extended the survival of treated mice in this very aggressive model (17 to 24 days, log-rank test p=0.038 compared to vehicle control) and decreased the expression of phospho-ERK (western blot, phospho-ERK), demonstrating that mirdametinib engaged its target in vivo. Testing against additional AT/RT orthotopic xenografts is currently underway. Our studies suggest that pharmacologically inhibiting the MAP kinase pathway may be an effective strategy to target AT/RT. Mirdametinib can potentially be an effective treatment to help extend survival in this deadly disease. Citation Format: Yiming Deng, Kristen Malebranche, Tyler Findlay, Anupa Geethadevi, Charles Eberhart, Jeffrey Rubens, Eric Raabe. MEK inhibitor mirdametinib suppresses MAP kinase pathway activity and inhibits tumor growth in atypical teratoid/rhabdoid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6498.