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Pan-KRAS inhibitor disables oncogenic signalling and tumour growth.

<div class='caption-title'>a, Chemical structures of the indicated compounds. b, Isogenic BaF3 cells expressing the indicated KRAS mutants were treated for 5 days in the absence of IL3 (oncogene dependent growth) to determine the effect on proliferation (mean ± s.e.m., n = 5, unless otherwise indicated, n denotes biological replicates). c, Cocrystal structures of drug-bound WT, G12C, G12D, G12V and G13D mutant KRAS. d,e, The effect of KRASi treatment on nucleotide exchange stimulated either by SOS1 (d) or EDTA (e). The reaction of KRAS G12C with the covalent inhibitor sotorasib is shown for comparison. A representative of two independent repeats is shown in d and e.</div>
<div class='caption-title'>a, RASless mouse embryonic fibroblasts expressing the indicated RAS isoforms were treated for 2 h. Cell extracts were subjected to RBD pull down and immunoblotting to determine the amount of active RAS. b, Sequence alignment of the G domain of RAS isoforms. c,d, Effect of isoform mimetic substitutions on RAS inhibition: RAS-GTP (c) and HRAS-GTP (d). HEK293 cells expressing the indicated mutants were treated for 2 h to determine the effect on RAS activation by using RBD pull down, immunoblotting and densitometry. e, Cocrystal structure of drug-bound KRAS showing H bonds between S122, N85 and K117 (black dotted lines, distance in Å). A representative of two independent experiments is shown in a, c and d.</div>
<div class='caption-title'>a, H358 cells were infected with a dox-inducible saturation mutagenesis library based on a KRAS G12C backbone and treated with either DMSO or KRASi for 2 weeks. The selection of mutations in amino acids far from drug-binding interface are shown (median, interquartile range and Tukey whiskers, n = 3). FC, fold change; T0, time 0. b, Residues from a were mapped in the cocrystal structure of KRAS G12C with the KRAS inhibitor. Residues involved in α5 contacts that were not identified in the screen are shown in black. Inset, 90° rotation. c, HEK293 cells expressing KRAS with a single G12C mutation or double mutants involving substitutions in the G4 and G5 motifs (top) or α5 helix contacts (bottom) were treated as shown for 2 h. Cell extracts were subjected to RBD pull down, immunoblotting and densitometry to determine the effect on KRAS-GTP concentrations. A representative of two independent repeats is shown in c.</div>
Kim D, Herdeis L, Rudolph D, Zhao Y, Böttcher J, Vides A, Ayala-Santos CI, Pourfarjam Y, Cuevas-Navarro A, Xue JY, Mantoulidis A, Bröker J, Wunberg T, Schaaf O, Popow J, Wolkerstorfer B, Kropatsch KG, Qu R, de Stanchina E, Sang B, Li C, McConnell DB, Kraut N, Lito P
OpenAccess logo Nature (2023)
Related entries: 8azv, 8azx, 8azy, 8azz, 8b00, 8onv

Cited: 20 times
EuropePMC logo PMID: 37258666

Abstract

KRAS is one of the most commonly mutated proteins in cancer, and efforts to directly inhibit its function have been continuing for decades. The most successful of these has been the development of covalent allele-specific inhibitors that trap KRAS G12C in its inactive conformation and suppress tumour growth in patients1-7. Whether inactive-state selective inhibition can be used to therapeutically target non-G12C KRAS mutants remains under investigation. Here we report the discovery and characterization of a non-covalent inhibitor that binds preferentially and with high affinity to the inactive state of KRAS while sparing NRAS and HRAS. Although limited to only a few amino acids, the evolutionary divergence in the GTPase domain of RAS isoforms was sufficient to impart orthosteric and allosteric constraints for KRAS selectivity. The inhibitor blocked nucleotide exchange to prevent the activation of wild-type KRAS and a broad range of KRAS mutants, including G12A/C/D/F/V/S, G13C/D, V14I, L19F, Q22K, D33E, Q61H, K117N and A146V/T. Inhibition of downstream signalling and proliferation was restricted to cancer cells harbouring mutant KRAS, and drug treatment suppressed KRAS mutant tumour growth in mice, without having a detrimental effect on animal weight. Our study suggests that most KRAS oncoproteins cycle between an active state and an inactive state in cancer cells and are dependent on nucleotide exchange for activation. Pan-KRAS inhibitors, such as the one described here, have broad therapeutic implications and merit clinical investigation in patients with KRAS-driven cancers.

Reviews citing this publication (10)

  1. Precision Oncology: 2023 in Review. Murciano-Goroff YR, Suehnholz SP, Drilon A, Chakravarty D. Cancer Discov 13 2525-2531 (2023)
  2. Prognostic and therapeutic impact of the KRAS G12C mutation in colorectal cancer. Qunaj L, May MS, Neugut AI, Herzberg BO. Front Oncol 13 1252516 (2023)
  3. The current landscape of using direct inhibitors to target KRASG12C-mutated NSCLC. Batrash F, Kutmah M, Zhang J. Exp Hematol Oncol 12 93 (2023)
  4. Current Standards, Multidisciplinary Approaches, and Future Directions in the Management of Extrahepatic Cholangiocarcinoma. Wheless M, Agarwal R, Goff L, Lockney N, Padmanabhan C, Heumann T. Curr Treat Options Oncol (2024)
  5. From bench to bedside: current development and emerging trend of KRAS-targeted therapy. Chen Y, Liu QP, Xie H, Ding J. Acta Pharmacol Sin (2023)
  6. Targeting CRAF kinase in anti-cancer therapy: progress and opportunities. Wang P, Laster K, Jia X, Dong Z, Liu K. Mol Cancer 22 208 (2023)
  7. Targeting KRAS in Colorectal Cancer: A Bench to Bedside Review. Bteich F, Mohammadi M, Li T, Bhat MA, Sofianidi A, Wei N, Kuang C. Int J Mol Sci 24 12030 (2023)
  8. Targeting KRAS in Pancreatic Ductal Adenocarcinoma: The Long Road to Cure. de Jesus VHF, Mathias-Machado MC, de Farias JPF, Aruquipa MPS, Jácome AA, Peixoto RD. Cancers (Basel) 15 5015 (2023)
  9. Targeting KRAS-Mutated Gastrointestinal Malignancies with Small-Molecule Inhibitors: A New Generation of Breakthrough Therapies. Caughey BA, Strickler JH. Drugs 84 27-44 (2024)
  10. The role of CRAF in cancer progression: from molecular mechanisms to precision therapies. Riaud M, Maxwell J, Soria-Bretones I, Dankner M, Li M, Rose AAN. Nat Rev Cancer (2024)

Articles citing this publication (10)

  1. Comment A non-covalent inhibitor with pan-KRAS potential. Kingwell K. Nat Rev Drug Discov 22 622 (2023)
  2. A single inhibitor for all KRAS mutations. Corcoran RB. Nat Cancer 4 1060-1062 (2023)
  3. ASD2023: towards the integrating landscapes of allosteric knowledgebase. He J, Liu X, Zhu C, Zha J, Li Q, Zhao M, Wei J, Li M, Wu C, Wang J, Jiao Y, Ning S, Zhou J, Hong Y, Liu Y, He H, Zhang M, Chen F, Li Y, He X, Wu J, Lu S, Song K, Lu X, Zhang J. Nucleic Acids Res 52 D376-D383 (2024)
  4. Decrypting Allostery in Membrane-Bound K-Ras4B Using Complementary In Silico Approaches Based on Unbiased Molecular Dynamics Simulations. Castelli M, Marchetti F, Osuna S, F Oliveira AS, Mulholland AJ, Serapian SA, Colombo G. J Am Chem Soc 146 901-919 (2024)
  5. Discovery of Hit Compounds Targeting the P4 Allosteric Site of K-RAS, Identified through Ensemble-Based Virtual Screening. Gomez-Gutierrez P, Rubio-Martinez J, Perez JJ. J Chem Inf Model 63 6412-6422 (2023)
  6. Facts and Hopes on RAS Inhibitors and Cancer Immunotherapy. Boumelha J, Molina-Arcas M, Downward J. Clin Cancer Res 29 5012-5020 (2023)
  7. Editorial In the literature: September 2023. Lamarca A, Moreno V, Gambardella V, Cervantes A. ESMO Open 8 102032 (2023)
  8. Mutant KRAS-activated circATXN7 fosters tumor immunoescape by sensitizing tumor-specific T cells to activation-induced cell death. Zhou C, Li W, Liang Z, Wu X, Cheng S, Peng J, Zeng K, Li W, Lan P, Yang X, Xiong L, Zeng Z, Zheng X, Huang L, Fan W, Liu Z, Xing Y, Kang L, Liu H. Nat Commun 15 499 (2024)
  9. Precision Oncology Comes of Age: Designing Best-in-Class Small Molecules by Integrating Two Decades of Advances in Chemistry, Target Biology, and Data Science. Stuart DD, Guzman-Perez A, Brooijmans N, Jackson EL, Kryukov GV, Friedman AA, Hoos A. Cancer Discov 13 2131-2149 (2023)
  10. Stromal-derived NRG1 enables oncogenic KRAS bypass in pancreas cancer. Han J, Xu J, Liu Y, Liang S, LaBella KA, Chakravarti D, Spring DJ, Xia Y, DePinho RA. Genes Dev 37 818-828 (2023)


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