10 Exploring the Role of Capicua (Cic) in Modulating Sensitivity to Mek Inhibitors in Glioblastoma

BACKGROUND Glioblastoma (GBM) is the most common and lethal primary brain tumor, with a median survival of 15 months. Standard therapies often fail due to intra-tumoral heterogeneity and resistance mechanisms, largely driven by hyperactive RTK/RAS/MEK/ERK signaling. Capicua (CIC), a tumor suppressor and HMG box transcription factor, represses oncogenic ETV1/4/5 but is degraded by aberrant ERK signaling in GBM, enabling tumor progression. CIC forms a co-repressor complex with Yin Yang 1 (YY1), a transcription factor that can act as a repressor or activator depending on its binding partner. This complex is essential for suppressing oncogenic transcription however it is destabilized in GBM. p90 ribosomal S6 kinase (p90RSK), a downstream ERK effector, has been implicated in tumor progression and therapy resistance. We hypothesize that p90RSK contributes to MEK inhibitor resistance by disrupting the CIC/YY1 complex, sustaining oncogenic transcription. METHODS Western blotting, qPCR, immunoprecipitation, and chromatin immunoprecipitation (ChIP-qPCR) were used to assess p90RSK’s effect on CIC/YY1 and its regulation of oncogenic targets. Cell viability assays and xenograft models evaluated the therapeutic potential of combined MEK and p90RSK inhibition. RESULTS MEK inhibition failed to restore CIC protein levels and did not suppress p90RSK activation, suggesting an alternative resistance mechanism. p90RSK destabilized the CIC/YY1 complex, leading to derepression of ETV1/4/5. Dual MEK and p90RSK inhibition restored CIC function, suppressed oncogenic transcription, and reduced tumor growth. CONCLUSION Targeting p90RSK overcomes MEK inhibitor resistance by restoring CIC/YY1 function, highlights a promising therapeutic strategy for GBM.