Quantitative Systems Pharmacology Analysis of KRAS G12C Covalent Inhibitors

CPT: Pharmacometrics & Systems Pharmacology
Edward C Stites, Andrey S Shaw

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.

References

Apr 19, 2002·Biochimica Et Biophysica Acta·Shane DonovanGideon Bollag
Oct 21, 2006·Systems Biology·N I MarkevichB N Kholodenko
Nov 7, 2006·Current Biology : CB·Sean BoykevischDafna Bar-Sagi
Oct 20, 2007·Science·Edward C StitesKodi S Ravichandran
Nov 16, 2007·Molecular Systems Biology·Marc R BirtwistleBoris N Kholodenko
Mar 18, 2008·Nature·Kian-Huat LimChristopher M Counter
Feb 12, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Edward C Stites, Kodi S Ravichandran
Jul 7, 2010·Cell·Uri MoranRon Milo
Sep 25, 2010·Advances in Experimental Medicine and Biology·Edward C Stites
Oct 28, 2010·JAMA : the Journal of the American Medical Association·Wendy De RoockSabine Tejpar
Jul 20, 2012·Nature·UNKNOWN Cancer Genome Atlas Network
Sep 18, 2012·Cell·Ramaswamy GovindanRichard K Wilson
Jan 22, 2013·Oncogene·H HuangC D Logsdon
Jan 31, 2013·Methods in Molecular Biology·Edward C Stites, Kodi S Ravichandran
Nov 22, 2013·Angewandte Chemie·Sang Min LimNathanael S Gray
Mar 22, 2014·Cancer Cell·Andrew G StephenFrank McCormick
May 8, 2014·Molecular Systems Biology·Christina Kiel, Luis Serrano
Jun 4, 2014·Proceedings of the National Academy of Sciences of the United States of America·John C HunterKenneth D Westover
Oct 18, 2014·Nature Reviews. Drug Discovery·Adrienne D CoxChanning J Der
Jan 21, 2015·Cell Reports·Edward C StitesKodi S Ravichandran
Jun 4, 2015·Molecular Cancer Research : MCR·John C HunterKenneth D Westover
Mar 10, 2016·Cancer Discovery·Kenneth D WestoverNathanael S Gray
Mar 16, 2016·Cancer Cell·G Aaron HobbsChanning J Der
Nov 4, 2016·Nature Reviews. Drug Discovery·Jonathan M L Ostrem, Kevan M Shokat
Jan 21, 2017·ACS Medicinal Chemistry Letters·Yuan XiongNathanael S Gray
Jun 18, 2017·Biochemistry·Lynn M McGregorKevan M Shokat
Aug 7, 2017·Cell Chemical Biology·Mei ZengNathanael S Gray
Feb 10, 2015·Cell Reports·Edward C StitesKodi S Ravichandran

❮ Previous
Next ❯

Citations

Oct 1, 2018·Oncology Research and Treatment·Savita Bisht, Georg Feldmann
Jan 9, 2020·Expert Opinion on Therapeutic Patents·Jason G Kettle, Doyle J Cassar
Sep 26, 2019·Science Signaling·Thomas McFallEdward C Stites
May 28, 2021·CPT: Pharmacometrics & Systems Pharmacology·Hiroyuki SayamaDaniel C Kirouac

❮ Previous
Next ❯

Methods Mentioned

BETA
GTPase
nucleotide
nucleotide exchange

Software Mentioned

MATLAB

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.