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Quantitative Systems Pharmacology Analysis of KRAS G12C Covalent Inhibitors

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...

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Detalles Bibliográficos
Autores principales: Stites, Edward C., Shaw, Andrey S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980551/
https://www.ncbi.nlm.nih.gov/pubmed/29484842
http://dx.doi.org/10.1002/psp4.12291
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author Stites, Edward C.
Shaw, Andrey S.
author_facet Stites, Edward C.
Shaw, Andrey S.
author_sort Stites, Edward C.
collection PubMed
description 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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spelling pubmed-59805512018-06-01 Quantitative Systems Pharmacology Analysis of KRAS G12C Covalent Inhibitors Stites, Edward C. Shaw, Andrey S. CPT Pharmacometrics Syst Pharmacol Research 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. John Wiley and Sons Inc. 2018-03-25 2018-05 /pmc/articles/PMC5980551/ /pubmed/29484842 http://dx.doi.org/10.1002/psp4.12291 Text en © 2018 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Research
Stites, Edward C.
Shaw, Andrey S.
Quantitative Systems Pharmacology Analysis of KRAS G12C Covalent Inhibitors
title Quantitative Systems Pharmacology Analysis of KRAS G12C Covalent Inhibitors
title_full Quantitative Systems Pharmacology Analysis of KRAS G12C Covalent Inhibitors
title_fullStr Quantitative Systems Pharmacology Analysis of KRAS G12C Covalent Inhibitors
title_full_unstemmed Quantitative Systems Pharmacology Analysis of KRAS G12C Covalent Inhibitors
title_short Quantitative Systems Pharmacology Analysis of KRAS G12C Covalent Inhibitors
title_sort quantitative systems pharmacology analysis of kras g12c covalent inhibitors
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980551/
https://www.ncbi.nlm.nih.gov/pubmed/29484842
http://dx.doi.org/10.1002/psp4.12291
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