ArticleCell reports2024
Cell-specific models reveal conformation-specific RAF inhibitor combinations that synergistically inhibit ERK signaling in pancreatic cancer cells.
Article in Cell reports, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- A structure-based modeling approach identifies effective drug combinations for RAS-mutant acute myeloid leukemia.iScience · 2026Article
- A catalogue of missense and nonsense mutation abundances for the U.S. cancer patient population.medRxiv : the preprint server for health sciences · 2026Article
- Mutant and Wild-Type RAS Cross-talk and Stoichiometric Deficiencies Are Determinants of Sensitivity to Targeted Therapies in KRASG12R Pancreatic Ductal Adenocarcinoma.Cancer research · 2026Article
- Dual RAF inhibition outperforms RAF-MEK combinations for suppressing ERK signaling in KRAS mutant cells.NPJ systems biology and applications · 2026Article
- Phase II Trial of Vemurafenib and Sorafenib Combination in AdvancedJournal of immunotherapy and precision oncology · 2026Article
- Article
- Mathematical modeling suggests 14-3-3 proteins modulate RAF paradoxical activation.PLoS computational biology · 2025Article
- Synergy and antagonism in the integration of BCR and CD40 signals that control B-cell population expansion.Molecular systems biology · 2025Article
- Ras, RhoA, and vascular pharmacology in neurodevelopment and aging.Neurochemistry international · 2024Review
- Potential Drug Synergy Through the ERBB2 Pathway in HER2+ Breast Tumors.International journal of molecular sciences · 2024Article
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Authors and funding
10 authors.
Funding
Abstract
Pancreatic ductal adenocarcinoma (PDAC) presents significant challenges for targeted clinical interventions due to prevalent KRAS mutations, rendering PDAC resistant to RAF and MEK inhibitors (RAFi and MEKi). In addition, responses to targeted therapies vary between patients. Here, we explored the differential sensitivities of PDAC cell lines to RAFi and MEKi and developed an isogenic pair comprising the most sensitive and resistant PDAC cells. To simulate patient- or tumor-specific variations, we constructed cell-line-specific mechanistic models based on protein expression profiling and differential properties of KRAS mutants. These models predicted synergy between two RAFi with different conformation specificity (type I½ and type II RAFi) in inhibiting phospho-ERK (ppERK) and reducing PDAC cell viability. This synergy was experimentally validated across all four studied PDAC cell lines. Our findings underscore the need for combination approaches to inhibit the ERK pathway in PDAC.
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