ID #659 Chromosome 6q Loss Mediated LATS1 Tumor Suppressor Deficiency is a Therapeutic Susceptibility for Ultra-High-Risk Posterior Fossa A Ependymoma

Background Posterior Fossa A (PFA) is the most frequent and clinically aggressive ependymoma (EPN) subgroup, with relapse typically representing a terminal event despite intensive multimodal therapy. Ultra-high-risk PFA EPNs are characterised by gain of chromosome 1q (1q+) and/or loss of 6q (6q-). While the molecular mechanism driving 1q+ has been elucidated, the pathobiology of 6q- PFA EPN remains poorly understood. Here we show that 6q loss in PFA EPN leads to the deletion ofLATS1(Large Tumor Suppressor Kinase 1), resulting in dysregulation of the Hippo signalling pathway and enhancedYAP/TEADactivity. Integrated analyses of primary and recurrent PFA EPNs, incorporating clinical, multi-omic, and functional assays were performed to define the biology and therapeutic susceptibility of 6q- PFA EPNs. Results In our cohort, cumulative 6q loss accounted for nearly half (18/40) of PFA EPN-related deaths. Copy number profiling identified theLATS1locus as recurrently deleted across all 6q- cases, including 10/60 with partial 6q deletions. Restoration ofLATS1expression in 6q- PFA cell lines re-established protein levels and suppressed proliferation. Tumor and RNA-seq analyses demonstrated marked Hippo pathway disruption with elevated YAP expression, andTEAD2-related transcriptional activity in PFA 6q-. TEAD palmitoylation inhibitors VT104 and VT107 exhibited PFA 6q- selective activityin vitro. In patient samples,TEAD2upregulation was further observed in a previously described undifferentiated, progenitor-like population of PFA EPN cells. Conclusions Loss of 6q defines an aggressive biological subset of PFA EPN associated with dismal clinical outcomes. Identification ofLATS1as a recurrently lost tumor suppressor implicates Hippo pathway dysregulation as a central driver of malignancy and we demonstrate YAP/TEAD signalling as a potential therapeutic target in this high-risk disease.