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Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy

Holderfield, Matthew ; Lee, Bianca J ; Jiang, Jingjing ; Tomlinson, Aidan ; Seamon, Kyle J ; Mira, Alessia ; Patrucco, Enrico ; Goodhart, Grace ; Dilly, Julien ; Gindin, Yevgeniy ; Dinglasan, Nuntana ; Wang, Yingyun ; Lai, Lick Pui ; Cai, Shurui ; Jiang, Lingyan ; Nasholm, Nicole ; Shifrin, Nataliya ; Blaj, Cristina ; Shah, Harshit ; Evans, James W ; Montazer, Nilufar ; Lai, Oliver ; Shi, Jade ; Ahler, Ethan ; Quintana, Elsa ; Chang, Stephanie ; Salvador, Anthony ; Marquez, Abby ; Cregg, Jim ; Liu, Yang ; Milin, Anthony ; Chen, Anqi ; Ziv, Tamar Bar ; Parsons, Dylan ; Knox, John E ; Klomp, Jennifer E ; Roth, Jennifer ; Rees, Matthew ; Ronan, Melissa ; Cuevas-Navarro, Antonio ; Hu, Feng ; Lito, Piro ; Santamaria, David ; Aguirre, Andrew J ; Waters, Andrew M ; Der, Channing J ; Ambrogio, Chiara ; Wang, Zhengping ; Gill, Adrian L ; Koltun, Elena S ; Smith, Jacqueline A M ; Wildes, David ; Singh, Mallika

Nature (London), 2024-05, Vol.629 (8013), p.919-926 [Periódico revisado por pares]

England: Nature Publishing Group

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Título:
Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy
Autor: Holderfield, Matthew ; Lee, Bianca J ; Jiang, Jingjing ; Tomlinson, Aidan ; Seamon, Kyle J ; Mira, Alessia ; Patrucco, Enrico ; Goodhart, Grace ; Dilly, Julien ; Gindin, Yevgeniy ; Dinglasan, Nuntana ; Wang, Yingyun ; Lai, Lick Pui ; Cai, Shurui ; Jiang, Lingyan ; Nasholm, Nicole ; Shifrin, Nataliya ; Blaj, Cristina ; Shah, Harshit ; Evans, James W ; Montazer, Nilufar ; Lai, Oliver ; Shi, Jade ; Ahler, Ethan ; Quintana, Elsa ; Chang, Stephanie ; Salvador, Anthony ; Marquez, Abby ; Cregg, Jim ; Liu, Yang ; Milin, Anthony ; Chen, Anqi ; Ziv, Tamar Bar ; Parsons, Dylan ; Knox, John E ; Klomp, Jennifer E ; Roth, Jennifer ; Rees, Matthew ; Ronan, Melissa ; Cuevas-Navarro, Antonio ; Hu, Feng ; Lito, Piro ; Santamaria, David ; Aguirre, Andrew J ; Waters, Andrew M ; Der, Channing J ; Ambrogio, Chiara ; Wang, Zhengping ; Gill, Adrian L ; Koltun, Elena S ; Smith, Jacqueline A M ; Wildes, David ; Singh, Mallika
Assuntos: Animals ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Bioavailability ; Cancer ; Cancer therapies ; Cell Line, Tumor ; Codons ; Female ; Genotypes ; Guanosine Triphosphate - metabolism ; Humans ; Inhibitors ; Isoforms ; K-Ras protein ; Male ; Mice ; Mutants ; Mutation ; Neoplasms - drug therapy ; Neoplasms - genetics ; Neoplasms - pathology ; Patients ; Proteins ; Proto-Oncogene Proteins p21(ras) - antagonists & inhibitors ; Proto-Oncogene Proteins p21(ras) - genetics ; Signal transduction ; Solid tumors ; Tumors ; Xenograft Model Antitumor Assays
É parte de: Nature (London), 2024-05, Vol.629 (8013), p.919-926
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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Descrição: 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 61 . 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 cancer . Nevertheless, KRAS mutations account for only around 15% of KRAS-mutated cancers , 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 (KRAS ). 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 KRAS 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).
Editor: England: Nature Publishing Group
Idioma: Inglês

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Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy

England: Nature Publishing Group

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