Abstract B022: TEAD inhibition overcomes YAP/TAZ-driven resistance to RAS(ON) inhibitors
Bibliographic record
Abstract
Abstract Acquired resistance poses a significant challenge to the long-term efficacy of RAS inhibitors in clinical settings (Awad et al, 2021). Genome-wide CRISPR screening efforts, conducted by us and others in the field, have identified key components of the Hippo pathway as major mediators of resistance to RAS inhibitors (Mukhopadhyay et al., 2023, Edwards et al., 2023). Specifically, the oncogenic transcriptional co-regulators YAP and TAZ, which require binding to the TEAD transcription factors to elicit their activity, have emerged as pivotal players in resistance mechanisms to MAPK pathway targeted therapies. In this work, we demonstrate that YAP overexpression is a driver of resistance to RAS(ON) multi-selective and RAS(ON) G12C-selective inhibitors. The YAP transcriptional signature is elevated in cells with acquired resistance to RAS(ON) inhibitors, and combination with TEAD inhibitors enhances their sensitivity to RAS(ON) inhibition. Notably, phosphoproteomics and imaging studies revealed that the YAP cytoplasmic retention mark is reduced upon treatment of cancer cells with RAS(ON) multi-selective inhibitor, leading to the translocation of YAP to the nucleus and its subsequent activation. Furthermore, a pan-TEAD inhibitor exhibits a high degree of synergy with RAS(ON) inhibitors in a panel of KRAS mutant cell lines in vitro. We are currently investigating the combination of RAS(ON) and TEAD inhibitors in vivo. Our studies support further investigation of combination strategies using RAS(ON) and TEAD inhibitors to mitigate the emergence of persister cells and overcome resistance to monotherapy. Citation Format: Vidyasiri Vemulapalli, Phuong Dinh, Mariela Moreno Ayala, Zheng Zhang, Mark Labrecque, Ida Aronchik, Jingjing Jiang, Mallika Singh, Elsa Quintana, Caroline Weller, David Wildes. TEAD inhibition overcomes YAP/TAZ-driven resistance to RAS(ON) inhibitors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr B022.
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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) | 0.004 | 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".