Journal Article

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

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

2024

Overview

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 1 . 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 2 , 3 . Nevertheless, KRAS G12C mutations account for only around 15% of KRAS -mutated cancers 4 , 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 ( KRAS G12X ). 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 G12C 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). RMC-7977, a compound that exhibits potent inhibition of the active states of mutant and wild-type KRAS, NRAS and HRAS variants has a strong anti-tumour effect on RAS-addicted tumours and is well tolerated in preclinical models.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/1 / 13/109 / 13/95 / 14 / 38 / 38/23 / 38/39 / 631/67/1059/153 / 631/67/1059/2326 / 631/67/1059/602 / 9/10 / Animals / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Bioavailability / Cancer / Cancer therapies / Cell Line, Tumor / Codons / Genotypes / GTP Phosphohydrolases / Guanosine Triphosphate - metabolism / Humanities and Social Sciences / Humans / Inhibitors / Isoforms / K-Ras protein / Lung cancer / Membrane Proteins / Mice / Mice, Inbred BALB C / Mice, Inbred C57BL / multidisciplinary / Mutants / Mutation / Neoplasms - drug therapy / Neoplasms - genetics / Neoplasms - pathology / Oncogene Protein p21(ras) - antagonists & inhibitors / Oncogene Protein p21(ras) - genetics / Patients / Piperazines - pharmacology / Piperazines - therapeutic use / Proteins / Proto-Oncogene Proteins p21(ras) - antagonists & inhibitors / Proto-Oncogene Proteins p21(ras) - genetics / Science / Science (multidisciplinary) / Signal transduction / Signal Transduction - drug effects / Solid tumors / Tumors / Xenograft Model Antitumor Assays