CSIG-25. EXPLORING THE ROLE OF THE CIC/YY1 COMPLEX IN MODULATING SENSITIVITY OF MEK INHIBITORS IN GLIOBLASTOMA
Bibliographic record
Abstract
Abstract BACKGROUND Glioblastoma (GBM) is the most common and aggressive primary brain tumor, with a median survival of just 15 months following diagnosis. Standard therapies remain largely ineffective due to pronounced intra-tumoral heterogeneity and rapid development of resistance mechanisms, underscoring the need for novel therapeutic approaches. A hallmark of GBM is hyperactivation of the RTK/RAS/MEK/ERK signaling pathway, which drives tumor growth and progression. One critical downstream effector is Capicua (CIC), a tumor suppressor and HMG box transcription factor. Normally, CIC represses oncogenic transcription factors such as ETV1, ETV4, and ETV5. In GBM, sustained ERK activity leads to CIC degradation, lifting this repression and promoting oncogene expression. While this mechanism is well characterized, our data indicates that CIC degradation persists even when ERK is pharmacologically inhibited, suggesting alternative regulatory mechanisms. A phospho-kinase array identified p90 ribosomal S6 kinase (p90RSK), a downstream ERK effector, as significantly upregulated following ERK inhibition. Notably, p90RSK has been implicated in regulating CIC function and contributing to resistance in other malignancies. Additionally, CIC forms a co-repressor complex with Yin Yang 1 (YY1), a multifunctional transcription factor. The stability of this complex is essential for repressing oncogenic programs; however, hyperactive RTK signaling may destabilize it, potentially via p90RSK-mediated mechanisms. METHODS Biochemical, molecular, and in vivo assays, including Western blotting, qPCR, immunoprecipitation, ChIP-qPCR, cell viability assays, and xenograft models, were used to assess p90RSK’s role in regulating CIC/YY1 function and GBM growth. RESULTS MEK inhibition alone failed to restore CIC levels or suppress p90RSK activation. p90RSK interacted with and destabilized the CIC/YY1 complex, derepressing ETV1/4/5. Dual MEK and p90RSK inhibition restored CIC function, suppressed oncogenic transcription, reduced GBM stem cell viability, and inhibited tumor growth. CONCLUSION p90RSK decreases GBM sensitivity to MEK inhibitors by destabilizing the CIC/YY1 complex and sustaining oncogenic transcription. Dual inhibition restores CIC function, suppresses oncogenic programs, and enhances therapeutic efficacy in GBM.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".