Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy Journal Article
| Authors: | Holderfield, M.; Lee, B. J.; Jiang, J.; Tomlinson, A.; Seamon, K. J.; Mira, A.; Patrucco, E.; Goodhart, G.; Dilly, J.; Gindin, Y.; Dinglasan, N.; Wang, Y.; Lai, L. P.; Cai, S.; Jiang, L.; Nasholm, N.; Shifrin, N.; Blaj, C.; Shah, H.; Evans, J. W.; Montazer, N.; Lai, O.; Shi, J.; Ahler, E.; Quintana, E.; Chang, S.; Salvador, A.; Marquez, A.; Cregg, J.; Liu, Y.; Milin, A.; Chen, A.; Ziv, T. B.; Parsons, D.; Knox, J. E.; Klomp, J. E.; Roth, J.; Rees, M.; Ronan, M.; Cuevas-Navarro, A.; Hu, F.; Lito, P.; Santamaria, D.; Aguirre, A. J.; Waters, A. M.; Der, C. J.; Ambrogio, C.; Wang, Z.; Gill, A. L.; Koltun, E. S.; Smith, J. A. M.; Wildes, D.; Singh, M. |
| Article Title: | Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy |
| Abstract: | RAS oncogenes (collectively NRAS, HRAS and especially KRAS) are among the most frequently mutated genes in cancer, with common driver mutations occurring at codons 12, 13 and 611. Small molecule inhibitors of the KRAS(G12C) oncoprotein have demonstrated clinical efficacy in patients with multiple cancer types and have led to regulatory approvals for the treatment of non-small cell lung cancer2,3. Nevertheless, KRASG12C mutations account for only around 15% of KRAS-mutated cancers4,5, and there are no approved KRAS inhibitors for the majority of patients with tumours containing other common KRAS mutations. Here we describe RMC-7977, a reversible, tri-complex RAS inhibitor with broad-spectrum activity for the active state of both mutant and wild-type KRAS, NRAS and HRAS variants (a RAS(ON) multi-selective inhibitor). Preclinically, RMC-7977 demonstrated potent activity against RAS-addicted tumours carrying various RAS genotypes, particularly against cancer models with KRAS codon 12 mutations (KRASG12X). Treatment with RMC-7977 led to tumour regression and was well tolerated in diverse RAS-addicted preclinical cancer models. Additionally, RMC-7977 inhibited the growth of KRASG12C cancer models that are resistant to KRAS(G12C) inhibitors owing to restoration of RAS pathway signalling. Thus, RAS(ON) multi-selective inhibitors can target multiple oncogenic and wild-type RAS isoforms and have the potential to treat a wide range of RAS-addicted cancers with high unmet clinical need. A related RAS(ON) multi-selective inhibitor, RMC-6236, is currently under clinical evaluation in patients with KRAS-mutant solid tumours (ClinicalTrials.gov identifier: NCT05379985). © The Author(s) 2024. |
| Keywords: | signal transduction; controlled study; protein expression; gene mutation; genetics; mutation; nonhuman; solid tumor; antineoplastic agents; antineoplastic agent; binding affinity; neoplasm; neoplasms; cell proliferation; mass spectrometry; mouse; animal; metabolism; animals; mice; pharmacodynamics; animal experiment; in vivo study; drug screening; pathology; xenograft model antitumor assays; cell line, tumor; inhibitor; cancer therapy; oncogene; tumor cell line; western blotting; fluorescence resonance energy transfer; ras protein; tumor; drug therapy; doxycycline; guanosine triphosphate; centrifugation; protein p21; proto-oncogene proteins p21(ras); kras protein, human; rna extraction; non small cell lung cancer; inhibition; cell; crystallography; electrospray mass spectrometry; liquid chromatography-mass spectrometry; estimated glomerular filtration rate; limit of quantitation; cancer; humans; human; male; female; article; cell viability assay; ec50; nci-h358 cell line; sotorasib; adagrasib; bicinchoninic acid assay |
| Journal Title: | Nature |
| Volume: | 629 |
| Issue: | 8013 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-05-23 |
| Start Page: | 919 |
| End Page: | 926 |
| Language: | English |
| DOI: | 10.1038/s41586-024-07205-6 |
| PUBMED: | 38589574 |
| PROVIDER: | scopus |
| PMCID: | PMC11111408 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF -- Source: Scopus |
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