Quantitative Systems Pharmacology Analysis of KRAS G12C Covalent Inhibitors.
نویسندگان
چکیده
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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A quantitative systems pharmacology analysis of KRAS G12C covalent inhibitors
The KRAS oncogene is the most common, activating, oncogenic mutation in human cancer. KRAS has proven difficult to target effectively. Two different strategies have recently been described for covalently targeting the most common activating KRAS mutant in lung cancer, KRAS G12C. Previously, we have developed a computational model of the processes that regulate Ras activation and this model has ...
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ورودعنوان ژورنال:
- CPT: pharmacometrics & systems pharmacology
دوره شماره
صفحات -
تاریخ انتشار 2018