Abstract 1216: Pan-RAS inhibition by a tumor-targeted biotherapeutic
Bibliographic record
Abstract
Abstract Oncogenic RAS signaling drives tumor growth in about 30% of human malignancies. In recent years the first mutant-specific inhibitors of KRAS G12C (sotorasib and adagrasib) entered the clinic. While some durable responses were noted in KRAS-mutant non-small cell lung cancer, the clinical experience of KRAS G12C inhibitors is marked by rapid drug resistance, either intrinsic or acquired, causing re-activation of the MAPK pathway. Common resistance mechanisms include compensatory signaling through the related RAS isoforms NRAS and HRAS, as well as the selection of non-G12C KRAS mutations, among others. The bacterial peptidase RRSP potently cleaves all RAS mutants and isoforms in the conserved Switch I region. We have shown that receptor-mediated intracellular delivery of RRSP using an engineered protein delivery system (RASx) can inactivate all RAS signaling in a cell, causing apoptosis in RAS-addicted tumor cells in vitro and in vivo. Since systemic pan-RAS inhibition is not likely to be tolerated therapeutically, precise tumor targeting is a necessary feature of a true pan-RAS inhibitor. Here, we describe the unique ability of the RASx system to specify the cell surface receptor used by RRSP to enter cells, allowing exquisite targeting and killing of KRAS, NRAS and HRAS-driven tumor cells while sparing healthy tissues. We screened a panel of patient-derived tumor organoids (PDOs), to demonstrate broad tumor cell killing across pancreatic and colorectal cancer-derived PDOs. 97% of KRAS mutant organoids were sensitive to RASx, independent of the specific mutation. Intriguingly, 46% of wildtype RAS PDOs were sensitive to RASx, including organoids with activating mutations in EGFR. In contrast, PDOs with mutations downstream of RAS such as BRAF V600E were resistant to RASx. Indeed, RASx is effective not only against RAS-addicted tumors, but also wildtype RAS tumors driven by upstream receptor tyrosine kinases, potentially expanding the clinical utility of this platform. RASx is a first-in-class, tumor-targeted pan-RAS inhibitor that represents a unique entry into the growing armamentarium against oncogenic RAS. Citation Format: Greg L. Beilhartz, Huazhu Liang, Molly Udaskin, Christine Ng, Nikolina Radulovich, Roman A. Melnyk. Pan-RAS inhibition by a tumor-targeted biotherapeutic [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1216.
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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) | 0.003 | 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".