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In Silico Study of the Acquired Resistance Caused by the Secondary Mutations of KRAS G12C Protein Using Long Time
1Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau SAR 999078, China.
Abstract:
Kirsten rat sarcoma viral oncogene homolog (KRAS) is a small GTPase protein which plays an important role in the treatment of KRAS mutant cancers. The FDA-approved AMG510 and MRTX849 (phase III clinical trials) are two potent KRASG12C-selective inhibitors that target KRAS G12C. However, the drug resistance caused by the second-site mutation in KRAS has emerged, and the mechanisms of drug resistance at atom level are still unclear. To clarify the mechanisms of drug resistance, we conducted long time molecular dynamics simulations (75 μs in total) to study the structural and energetic features of KRAS G12C and its four drug resistant variants to inhibitors. The combined binding free energy calculation and protein-ligand interaction fingerprint revealed that these second-site mutations indeed caused KRAS to produce different degrees of resistance to AMG510 and MRTX849. Furthermore, Markov State Models and 2D-free energy landscapes analysis revealed the difference in conformational changes of mutated KRAS bound with and without inhibitors. Furthermore, the comparative analysis of these systems showed that there were differences in their allosteric signal pathways. These findings provide the molecular mechanism of drug resistance, which helps to guide novel KRAS G12C inhibitor design to overcome drug resistance.
Insights
Drug resistance in KRAS G12C cancers can arise from second-site mutations. Molecular dynamics simulations reveal how these mutations alter KRAS structure and inhibitor binding, guiding the development of new KRAS G12C therapies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Kirsten rat sarcoma viral oncogene homolog (KRAS) is crucial in KRAS-mutant cancer treatment.
- KRAS G12C-selective inhibitors like AMG510 and MRTX849 show promise but face emerging drug resistance.
- The atomic-level mechanisms driving this drug resistance remain largely unelucidated.
Purpose of the Study:
- To investigate the molecular mechanisms of drug resistance in KRAS G12C variants.
- To elucidate the structural and energetic basis for resistance to AMG510 and MRTX849.
Main Methods:
- Utilized extensive molecular dynamics (MD) simulations (75 μs total).
- Employed binding free energy calculations and protein-ligand interaction fingerprinting.
- Applied Markov State Models (MSM) and 2D-free energy landscape analysis.
Main Results:
- Second-site KRAS mutations confer varying degrees of resistance to AMG510 and MRTX849.
- Mutations induce distinct conformational changes in KRAS when bound to inhibitors.
- Comparative analysis identified differences in allosteric signal pathways among resistant variants.
Conclusions:
- The study provides a detailed molecular understanding of KRAS G12C inhibitor resistance.
- Findings offer insights into the structural and dynamic alterations driving resistance.
- This knowledge can guide the design of next-generation KRAS G12C inhibitors to overcome resistance.
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