The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity
Jude Canon1, Karen Rex2, Anne Y Saiki2
1Amgen Research, Amgen Inc, Thousand Oaks, CA, USA. jcanon@amgen.com.
Abstract:
KRAS is the most frequently mutated oncogene in cancer and encodes a key signalling protein in tumours1,2. The KRAS(G12C) mutant has a cysteine residue that has been exploited to design covalent inhibitors that have promising preclinical activity3-5. Here we optimized a series of inhibitors, using novel binding interactions to markedly enhance their potency and selectivity. Our efforts have led to the discovery of AMG 510, which is, to our knowledge, the first KRAS(G12C) inhibitor in clinical development. In preclinical analyses, treatment with AMG 510 led to the regression of KRASG12C tumours and improved the anti-tumour efficacy of chemotherapy and targeted agents. In immune-competent mice, treatment with AMG 510 resulted in a pro-inflammatory tumour microenvironment and produced durable cures alone as well as in combination with immune-checkpoint inhibitors. Cured mice rejected the growth of isogenic KRASG12D tumours, which suggests adaptive immunity against shared antigens. Furthermore, in clinical trials, AMG 510 demonstrated anti-tumour activity in the first dosing cohorts and represents a potentially transformative therapy for patients for whom effective treatments are lacking.
Insights
Researchers developed AMG 510, a novel KRAS(G12C) inhibitor, showing significant anti-tumour activity in preclinical models and early clinical trials. This targeted therapy offers new hope for cancer patients with KRAS mutations.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- KRAS is a frequently mutated oncogene in cancer, driving tumor growth.
- The KRAS(G12C) mutation presents a targetable cysteine residue for inhibitor development.
Purpose of the Study:
- To optimize covalent inhibitors targeting KRAS(G12C) for enhanced potency and selectivity.
- To evaluate the therapeutic potential of the novel inhibitor AMG 510 in preclinical and clinical settings.
Main Methods:
- Structure-based drug design to optimize inhibitor binding interactions.
- Preclinical studies in KRAS(G12C) tumor models (in vitro and in vivo).
- Clinical trials to assess safety and efficacy of AMG 510.
Main Results:
- Discovery of AMG 510, the first KRAS(G12C) inhibitor in clinical development.
- AMG 510 demonstrated significant tumor regression and enhanced efficacy with chemotherapy and targeted agents.
- AMG 510 induced a pro-inflammatory tumor microenvironment, leading to durable cures and adaptive immunity in mice.
Conclusions:
- AMG 510 exhibits potent and selective inhibition of KRAS(G12C).
- AMG 510 shows promising anti-tumor activity and potential as a transformative therapy for KRAS(G12C) cancers.
- The development of AMG 510 represents a significant advancement in targeted cancer therapy.
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