PATH-37. SPATIAL GENE EXPRESSION PROGRAMS AND PROTEIN SIGNALING MECHANISMS DRIVE MENINGIOMA EVOLUTION AND THERAPEUTIC VULNERABILITY

Abstract Intratumor heterogeneity drives cancer evolution and resistance to therapy, but unbiased approaches elucidate mechanisms driving intratumor have been lacking. Here, we integrate spatial gene expression programs protein signaling across 16 meningioma samples define how molecular classification, temporal evolution, or of the most common primary intracranial tumor. Spatial transcriptomic analysis was performed on 38,718 regions profiling 72 proteins comprising proliferation, stress, microenvironment, immune, modules 82 regions. DNA methylation, copy number variant, targeted profiling, sequencing, histologic, immunohistochemical analyses (Ki67, H3K27me3, p16) were all meningiomas study in context pre-existing classification schemes. Primary cells, CRISPR interference, pharmacology, 3D co-culture models used for mechanistic functional validation. revealed significant intertumor irrespective histologic subtype grade, methylation group (Merlin-intact, Immune-enriched, Hypermitotic), variant (1p loss, 1q gain, 6p 9p 14q 22q loss), risk score, driver mutation (NF2, CDKN2A/B, TERT promoter, BAP1, SMARCB1, ARID1A). paired histologically molecularly distinct from individual (n=4), recurrent (n=9), conserved underlying evolution. Mechanistic studies validated therapeutic vulnerabilities clusters combinations FDA-approved small molecules inhibiting cell cycle (abemaciclib), epigenetic regulators (vorinostat), damage response (nariparib), MAPK (erlotinib, selumetinib), PI3K-AKT (copanlisib). In summary, these data vulnerability, shedding light past clinical failures elucidating novel concurrent sequential therapies treat that are resistant standard interventions.