CSIG-23. CIC PROTEIN INSTABILITY DRIVES CANCER PHENOTYPES IN GLIOBLASTOMA
Bibliographic record
Abstract
The aggressive nature of glioblastoma (GBM) has been attributed to hyperactivation of receptor tyrosine kinases (RTK) and their downstream signaling pathways including Ras/ERK. Pharmacological agents directed against membrane bound RTKs and cytoplasmic kinases within the Ras/ERK signaling pathway have shown promise pre-clinically, but success is yet to be realized in clinical trials. Because cancer is a disease associated with aberrant gene expression patterns, transcription factors that serve as the convergence points of oncogenic signaling hold great therapeutic promise. However, this has not yet been explored in the context of Ras/ERK signaling in GBM. The HMG-box transcriptional repressor, capicua (CIC), has recently emerged as a conserved nuclear sensor of RTK signaling in Drosophila and mammals. CIC represses EGFR/Ras/ERK pathway-responsive genes, keeping them silent in the absence of signaling. Despite the clear genetic evidence and its connection to one of the most important pathways in cancer, molecular mechanisms governing CIC regulation and its involvement in cancer remain poorly characterized. In GBM, unlike in oligodendroglioma (OD), CIC is not mutated. Surprisingly, we find substantial downregulation of wild type CIC protein despite intact mRNA expression in human GBM tumor samples. Here, we identify the nuclear E3-ubiquitin ligase responsible for the degradation of CIC in response to EGFR/Ras/ERK signaling. Interestingly, common disease-causing CIC variants fail to be ubiquitylated in response to Ras/ERK activation. Creation of a degradation-resistant form of CIC, unresponsive to upstream Ras/ERK signaling, reduced tumor growth and sensitized GBM cells to the effects of Ras/ERK inhibition. Our mechanistic insights into regulation of CIC provides rationale for alternative therapeutic strategies aimed at stabilizing CIC and activating its repressor function in GBM and other Ras/ERK-driven tumors.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| 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 | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".