The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).
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Holderfield, M. et al. Nature. 629, 919–926 (2024).
doi: 10.1038/s41586-024-07205-6.
Summary of the findings
Summary of the findingsKRAS mutations occur in approximately 30% of all human cancers, and frequently in pancreas, colon and lung tumors. Small molecule inhibitors that specifically target the inactive (OFF) state of KRAS G12C mutant proteins have demonstrated clinical efficacy in NSCLC, yet patients eventually progress and treatment resistant tumors frequently harbor non-G12C RAS mutations or other RAS pathway mutations. Notably, there are no approved RAS-targeted therapy options for the majority of patients with non-G12C RAS mutant cancers, in particular patients with PDAC of whom over 90% have RAS mutant tumors. Therefore, there is a significant unmet medical need for a direct RAS inhibitor that targets multiple oncogenic RAS mutations as a potential therapeutic strategy for KRAS addicted cancers.
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RMC-7977 is a potent RAS(ON) multi-selective, noncovalent tri-complex small molecule
inhibitor that is selective for the active, GTP-bound state of both mutant and wild-type variants of the canonical RAS isoforms (KRAS, NRAS and HRAS). RMC-7977 forms a tri-complex with RAS(ON) and cyclophilin A (CypA), disrupting RAS effector binding through steric occlusion. RMC-7977 binds to the switch I effector binding domain and occupies a binding pocket between RAS(ON) and CypA. This pocket leaves a groove containing common oncogenic mutational hotspots G12, G13 and Q61 unoccupied, providing a structural basis for tri-complex formation with, and inhibition of, multiple RAS-GTP variants by RMC-7977.
RMC-7977 is a potent RAS(ON) multi-selective, noncovalent tri-complex small molecule
inhibitor that is selective for the active, GTP-bound state of both mutant and wild-type variants of the canonical RAS isoforms (KRAS, NRAS and HRAS). RMC-7977 forms a tri-complex with RAS(ON) and cyclophilin A (CypA), disrupting RAS effector binding through steric occlusion. RMC-7977 binds to the switch I effector binding domain and occupies a binding pocket between RAS(ON) and CypA. This pocket leaves a groove containing common oncogenic mutational hotspots G12, G13 and Q61 unoccupied, providing a structural basis for tri-complex formation with, and inhibition of, multiple RAS-GTP variants by RMC-7977.
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RMC-7977 potently inhibits proliferation in RAS-addicted cancer cells in vitro. Consistent with this mechanism of action, in a large panel of >800 cancer cell lines, KRAS G12X and NRAS Q61X mutant cancer cell lines were associated with RMC-7977 sensitivity while BRAF V600E mutant cells correlated with resistance. In vivo, oral administration of RMC-7977 potently inhibited RAS pathway activation in tumors and induced tumor regressions in multiple KRAS mutant human xenograft models in mice. Preclinical data also demonstrate that RMC-7977 has the potential to overcome many of the resistance mechanisms observed clinically for KRASG12C(OFF) inhibitors.
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Together, these preclinical data demonstrate the structural and biochemical mechanism of
action for RMC-7977 and support the clinical evaluation of RAS(ON) multi-selective tricomplex inhibitors, like the investigational agent RMC-6236, for the treatment of RAS addicted cancers.
action for RMC-7977 and support the clinical evaluation of RAS(ON) multi-selective tricomplex inhibitors, like the investigational agent RMC-6236, for the treatment of RAS addicted cancers.
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