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Published on: January 17, 2019
Targeting active RAS with molecular glue
1The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China.
Abstract:
Activating mutations in RAS genes, notably KRASG12C, are pervasive in numerous cancers, presenting formidable challenges to therapy due to their elusive druggability. The landmark discovery of KRASG12C allosteric inhibitors marked a transformative milestone in cancer treatment, resulting in the approval of sotorasib and adagrasib. However, limitations in the depth and duration of response prompted the quest for alternative strategies. Recently, Holderfield et al., Wasko et al., and Jiang et al. reported on tri-complex inhibitors, namely RMC-7977 and RMC-6236, targeting activated RAS variants, demonstrating promising preclinical efficacy surpassing adagrasib. These advancments signify a paradigm shift in RAS oncology, promising enduring therapeutic benefits and warranting further clinical exploration.
Insights
New tri-complex inhibitors targeting KRASG12C mutations show superior preclinical efficacy compared to existing therapies. These advancements offer a promising paradigm shift in RAS-targeted cancer treatment, potentially leading to more durable patient benefits.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Activating RAS gene mutations, particularly KRASG12C, are common in many cancers and historically difficult to target therapeutically.
- The development of KRASG12C allosteric inhibitors (sotorasib, adagrasib) represented a significant advance, but limitations in response depth and duration necessitate further innovation.
Purpose of the Study:
- To explore novel therapeutic strategies for cancers driven by RAS mutations.
- To evaluate the preclinical efficacy of new tri-complex inhibitors targeting activated RAS variants.
Main Methods:
- Preclinical evaluation of novel tri-complex inhibitors (RMC-7977, RMC-6236).
- Comparative efficacy studies against existing KRASG12C inhibitors like adagrasib.
Main Results:
- The novel tri-complex inhibitors demonstrated promising preclinical efficacy.
- These new agents showed superior performance compared to adagrasib in preclinical models.
Conclusions:
- Tri-complex inhibitors represent a significant advancement in RAS-targeted cancer therapy.
- These findings suggest a potential paradigm shift in RAS oncology, offering improved therapeutic benefits.
- Further clinical investigation of these novel inhibitors is warranted.
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