Progress in Targeting KRAS Directly

Overview

Journal Methods Mol Biol

Specialty Molecular Biology

Date 2024 Apr 3

PMID 38570448

Authors

Dwight V Nissley

Andrew G Stephen

Ming Yi

Frank McCormick

Affiliations

Soon will be listed here.

Abstract

RAS research has entered the world of translational and clinical science. Progress has been based on our appreciation of the role of RAS mutations in different types of cancer and the effects of these mutations on the biochemical, structural, and biophysical properties of the RAS proteins themselves, particularly KRAS, on which most attention has been focused. This knowledge base, while still growing, has enabled creative chemical approaches to targeting KRAS directly. Our understanding of RAS signaling pathways in normal and cancer cells plays an important role for developing RAS inhibitors but also continues to reveal new approaches to targeting RAS through disruption of signaling complexes and downstream pathways.

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References

Prior I, Hood F, Hartley J . The Frequency of Ras Mutations in Cancer. Cancer Res. 2020; 80(14):2969-2974. PMC: 7367715. DOI: 10.1158/0008-5472.CAN-19-3682. View

Prior I, Lewis P, Mattos C . A comprehensive survey of Ras mutations in cancer. Cancer Res. 2012; 72(10):2457-67. PMC: 3354961. DOI: 10.1158/0008-5472.CAN-11-2612. View

Gibbs J, Sigal I, Poe M, Scolnick E . Intrinsic GTPase activity distinguishes normal and oncogenic ras p21 molecules. Proc Natl Acad Sci U S A. 1984; 81(18):5704-8. PMC: 391779. DOI: 10.1073/pnas.81.18.5704. View

Vetter I, Wittinghofer A . The guanine nucleotide-binding switch in three dimensions. Science. 2001; 294(5545):1299-304. DOI: 10.1126/science.1062023. View

Huang W, Alvarez S, Kondo Y, Kuriyan J, Groves J . Relating cellular signaling timescales to single-molecule kinetics: A first-passage time analysis of Ras activation by SOS. Proc Natl Acad Sci U S A. 2021; 118(45). PMC: 8694064. DOI: 10.1073/pnas.2103598118. View

Margarit S, Bar-Sagi D, Kuriyan J . The structural basis of the activation of Ras by Sos. Nature. 1998; 394(6691):337-43. DOI: 10.1038/28548. View

Traut T . Physiological concentrations of purines and pyrimidines. Mol Cell Biochem. 1994; 140(1):1-22. DOI: 10.1007/BF00928361. View

Scheffzek K, Lautwein A, Kabsch W, Ahmadian M, Wittinghofer A . Crystal structure of the GTPase-activating domain of human p120GAP and implications for the interaction with Ras. Nature. 1996; 384(6609):591-6. DOI: 10.1038/384591a0. View

Ahmadian M, Hoffmann U, Goody R, Wittinghofer A . Individual rate constants for the interaction of Ras proteins with GTPase-activating proteins determined by fluorescence spectroscopy. Biochemistry. 1997; 36(15):4535-41. DOI: 10.1021/bi962556y. View

10.

Bandaru P, Kondo Y, Kuriyan J . The Interdependent Activation of Son-of-Sevenless and Ras. Cold Spring Harb Perspect Med. 2018; 9(2). PMC: 6360870. DOI: 10.1101/cshperspect.a031534. View

11.

Seeburg P, Colby W, Capon D, Goeddel D, Levinson A . Biological properties of human c-Ha-ras1 genes mutated at codon 12. Nature. 1984; 312(5989):71-5. DOI: 10.1038/312071a0. View

12.

Der C, Finkel T, Cooper G . Biological and biochemical properties of human rasH genes mutated at codon 61. Cell. 1986; 44(1):167-76. DOI: 10.1016/0092-8674(86)90495-2. View

13.

Rabara D, Tran T, Dharmaiah S, Stephens R, McCormick F, Simanshu D . KRAS G13D sensitivity to neurofibromin-mediated GTP hydrolysis. Proc Natl Acad Sci U S A. 2019; 116(44):22122-22131. PMC: 6825300. DOI: 10.1073/pnas.1908353116. View

14.

Smith M, Neel B, Ikura M . NMR-based functional profiling of RASopathies and oncogenic RAS mutations. Proc Natl Acad Sci U S A. 2013; 110(12):4574-9. PMC: 3607025. DOI: 10.1073/pnas.1218173110. View

15.

Poulin E, Bera A, Lu J, Lin Y, Strasser S, Paulo J . Tissue-Specific Oncogenic Activity of KRAS. Cancer Discov. 2019; 9(6):738-755. PMC: 6548671. DOI: 10.1158/2159-8290.CD-18-1220. View

16.

Burge R, Hobbs G . Not all RAS mutations are equal: A detailed review of the functional diversity of RAS hot spot mutations. Adv Cancer Res. 2022; 153:29-61. DOI: 10.1016/bs.acr.2021.07.004. View

17.

Donovan S, Shannon K, Bollag G . GTPase activating proteins: critical regulators of intracellular signaling. Biochim Biophys Acta. 2002; 1602(1):23-45. DOI: 10.1016/s0304-419x(01)00041-5. View

18.

Zhao Q, Fujimiya R, Kubo S, Marshall C, Ikura M, Shimada I . Real-Time In-Cell NMR Reveals the Intracellular Modulation of GTP-Bound Levels of RAS. Cell Rep. 2020; 32(8):108074. DOI: 10.1016/j.celrep.2020.108074. View

19.

John J, Frech M, Wittinghofer A . Biochemical properties of Ha-ras encoded p21 mutants and mechanism of the autophosphorylation reaction. J Biol Chem. 1988; 263(24):11792-9. View

20.

John J, Schlichting I, Schiltz E, Rosch P, Wittinghofer A . C-terminal truncation of p21H preserves crucial kinetic and structural properties. J Biol Chem. 1989; 264(22):13086-92. View