Atrt-17. Inhibiting the Map Kinase Pathway With Mek Inhibitor Mirdametinib Suppresses Cancer Growth in Atypical Teratoid/Rhabdoid Tumors

Abstract BACKGROUND Atypical teratoid/rhabdoid tumors (ATRT) are poor-prognosis infantile brain tumors. Our prior studies examining ATRT primary tissues have shown an increased expression of phospho-ERK, a downstream effector of MEK in the mitogen-activated protein kinase (MAPK) pathway. The elevated MAPK pathway potentially contributes to drug resistance, aggressive cancer growth, and poor treatment outcomes. Mirdametinib is a highly specific MEK1/2 inhibitor reported to have superior blood-brain-barrier penetration compared to other MEK inhibitors. We hypothesized that mirdametinib can suppress ATRT tumor growth and improve overall survival. METHODS Mirdametinib effects were assessed through western blot for MAPK markers. Western blot analysis, Muse flow cytometer assays, and immunofluorescence were used for proliferation and apoptosis. Mirdametinib impact on survival was determined in orthotopic xenograft models of ATRT. RESULTS Mirdametinib decreased MAPK pathway activity in five ATRT cell lines (western blot: phospho-ERK). Cell lines treated with mirdametinib exhibited lower rates of proliferation (western blot: phospho-Rb; BrdU immunofluorescence staining: CHLA05 p=0.015, CHLA06 p0.0001, BT37 p0.0001 compared to DMSO control by t-test). Mirdametinib induced apoptosis in ATRT cells (western blot: cPARP; Muse Annexin V Assay: CHLA04, CHLA05, CHLA06, and BT37, p0.0001, CHLA266, p0.01 compared to DMSO control by t-test; cleaved caspase-3 immunofluorescence staining: CHLA05, CHLA06, and BT37, p0.0001 compared to DMSO control by t-test). Daily oral delivery of mirdametinib treatment significantly extended the survival of mice bearing the very aggressive orthotopic CHLA06 tumors (17 to 24 days, log-rank test p=0.038 compared to vehicle control) and decreased the expression of phospho-ERK (western blot). Testing against additional ATRT orthotopic xenografts is currently underway. CONCLUSIONS Mirdametinib inhibits the MAPK pathway both in vitro and in vivo, suppressing proliferation and inducing apoptosis in ATRT. Our studies suggest that pharmacologically inhibiting the MAPK pathway with mirdametinib may be an effective strategy to target ATRT and help extend survival in this deadly disease.