ArticleCPT: pharmacometrics & systems pharmacology2018
Quantitative Systems Pharmacology Analysis of KRAS G12C Covalent Inhibitors.
Article in CPT: pharmacometrics & systems pharmacology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
14 citing papers in PubMed.
- Mathematical modeling suggests 14-3-3 proteins modulate RAF paradoxical activation.PLoS computational biology · 2025Article
- Preclinical Evaluation of [ACS pharmacology & translational science · 2024Article
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- Computational modeling of drug response identifies mutant-specific constraints for dosing panRAF and MEK inhibitors in melanoma.bioRxiv : the preprint server for biology · 2024Article
- Systems modeling of oncogenic G-protein and GPCR signaling reveals unexpected differences in downstream pathway activation.NPJ systems biology and applications · 2024Article
- Direct GDP-KRASTherapeutic advances in medical oncology · 2023Review
- Computational Random Mutagenesis to Investigate RAS Mutant Signaling.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Co-targeting KRAS G12C and EGFR reduces both mutant and wild-type RAS-GTP.NPJ precision oncology · 2022Article
- Identification of RAS mutant biomarkers for EGFR inhibitor sensitivity using a systems biochemical approach.Cell reports · 2021Article
- Article
- Virtual clinical trial simulations for a novel KRASCPT: pharmacometrics & systems pharmacology · 2021Article
- Capturing Biomarkers and Molecular Targets in Cellular Landscapes From Dynamic Reaction Network Models and Machine Learning.Frontiers in oncology · 2021Review
- Mathematical Modeling to Study KRAS Mutant-Specific Responses to Pathway Inhibition.Methods in molecular biology (Clifton, N.J.) · 2021Article
- A systems mechanism for KRAS mutant allele-specific responses to targeted therapy.Science signaling · 2019Article
Corrections and comments
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Authors and funding
2 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
KRAS has proven difficult to target pharmacologically. Two strategies have recently been described for covalently targeting the most common KRAS mutant in lung cancer, KRAS G12C. Previously, we developed a computational model of the processes that regulate Ras activation. Here, we use this model to investigate KRAS G12C covalent inhibitors. We updated the model to include Ras protein turnover, and validation demonstrates that our model performs well in areas of G12C targeting where conventional wisdom struggles. We then used the model to investigate possible strategies to improve KRAS G12C inhibitors and identified GEF loading as a mechanism that could improve efficacy. Our simulations also found resistance-promoting mutations may reverse which class of KRAS G12C inhibitor inhibits the system better, suggesting that there may be value to pursuing both types of KRAS G12C inhibitors. Overall, this work demonstrates areas in which systems biology approaches can inform Ras drug development.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.