Abstract 4398: MEK inhibitors prevent rebound reactivation of ERK signaling by the RAF inhibitor PLX4032 and enhance its antitumor activity
Bibliographic record
Abstract
Abstract Activation of ERK signaling occurs in the majority of melanomas and tumors with BRAF mutation are especially sensitive to its inhibition with MEK or RAF inhibitors. The latter inhibit ERK signaling only in tumors with V600E mutant BRAF and activate the pathway in cells with WT BRAF. These data implied that RAF inhibitors would have a wider therapeutic index than MEK inhibitors with a greater therapeutic effect, but could also cause toxicity by activating the ERK pathway in normal tissue. These predictions were born out in clinical trials, in which the RAF inhibitor PLX4032 caused tumor regression in most patients with metastatic melanoma with mutant BRAF, but also caused squamous cell carcinoma of the skin in one third of patients. Unfortunately, these responses are rarely complete and the median time to relapse is approximately nine months. We now find that prolonged treatment of BRAF mutant cells with PLX4032 is associated with a rebound of ERK phosphorylation from its nadir that is associated with an increase in the transcriptional output of the pathway and could therefore limit the therapeutic effects of the drug. In this new steady state, ERK phosphorylation and output are sensitive to MEK inhibitors but not readdition of RAF inhibitors. The rebound of ERK signaling is associated with upstream activation in the RAS pathway. We therefore determined the effects of combined RAF and MEK kinase inhibition in a panel of melanoma cells with mutant BRAF. Combined inhibition delayed pathway rebound and resulted in more prolonged suppression of ERK output, enhanced cell death, and tumor growth inhibition compared to treatment with the RAF inhibitor alone. These results suggest that combined RAF and MEK kinase inhibition may be a useful strategy to improve the extent and duration of responses to RAF inhibitors and minimize toxicity caused by ERK activation in normal tissue. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4398. doi:10.1158/1538-7445.AM2011-4398
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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) | 0.001 | 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) | 0.005 | 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".