Pan-KRAS inhibitor disables oncogenic signalling and tumour growth Journal Article
| Authors: | Kim, D.; Herdeis, L.; Rudolph, D.; Zhao, Y.; Böttcher, J.; Vides, A.; Ayala-Santos, C. I.; Pourfarjam, Y.; Cuevas-Navarro, A.; Xue, J. Y.; Mantoulidis, A.; Bröker, J.; Wunberg, T.; Schaaf, O.; Popow, J.; Wolkerstorfer, B.; Kropatsch, K. G.; Qu, R.; de Stanchina, E.; Sang, B.; Li, C.; McConnell, D. B.; Kraut, N.; Lito, P. |
| Article Title: | Pan-KRAS inhibitor disables oncogenic signalling and tumour growth |
| 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. © 2023, The Author(s). |
| Keywords: | signal transduction; controlled study; unclassified drug; human cell; genetics; mutation; nonhuman; pancreas cancer; binding affinity; neoplasm; neoplasms; colorectal cancer; cell proliferation; animal cell; mouse; animal; animals; mice; amino acid substitution; serine; embryo; animal experiment; animal model; body weight; lung cancer; antineoplastic activity; drug potency; drug structure; tumor xenograft; inhibitor; drug design; wild type; carcinogenesis; fibroblast; pancreas adenocarcinoma; isoleucine; alanine; tumor growth; tumor; leucine; k ras protein; glutamic acid; protein p21; proto-oncogene proteins p21(ras); aspartic acid; drug protein binding; glutamine; lysine; protein inhibitor; cysteine; glycine; drug exposure; phenylalanine; valine; mutant; gtp phosphohydrolases; nucleotide; inhibition; cell; nucleotides; antiproliferative activity; guanosine triphosphatase; drug; colorectal adenocarcinoma; pancreatic ductal carcinoma; cancer; human; female; article; hek293 cell line; ic50; mia paca-2 cell line; ba/f3 cell line; sotorasib; adagrasib; bi 0474; bi 2493; bi 2865; cecal adenocarcinoma; hpac cell line; ls513 cell line; sw620 cell line |
| Journal Title: | Nature |
| Volume: | 619 |
| Issue: | 7968 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2023-07-06 |
| Start Page: | 160 |
| End Page: | 166 |
| Language: | English |
| DOI: | 10.1038/s41586-023-06123-3 |
| PUBMED: | 37258666 |
| PROVIDER: | scopus |
| PMCID: | PMC10322706 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Piro Lito -- Source: Scopus |
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