Characterization of KRASG12C inhibitor olomorasib single-agent and combination with activity in KRASG12C-mutant
Shengbin Peng1, Youyan Zhang1, Xi Lin1
1Eli Lilly and Company, Indianapolis, IN, USA.
Abstract:
The impact of first-generation covalent KRASG12C inhibitors has been reduced due to the development of drug resistance, tolerability and challenges combining with immunotherapy. We designed olomorasib, a next-generation GDP-binding KRASG12C inhibitor, for nanomolar potency as well as selectivity over wild-type inhibition. In both in vitro and in vivo models of KRASG12C -mutant cancers, olomorasib reduces RAS activity and pERK levels, leading to substantial and significant tumor growth inhibition. Additionally, olomorasib combined with immune checkpoint inhibitors demonstrates greater anti-tumor activity compared to monotherapy. Furthermore, we demonstrate that olomorasib binds tightly to KRASG12C even in the presence of clinically relevant second site mutations, a known mechanism of resistance and limitation to currently approved KRASG12C inhibitors. These findings suggest that olomorasib could be effective for patients with KRASG12C mutant cancers either as monotherapy or in combination with immunotherapy. Olomorasib monotherapy and combination treatments are currently being investigated clinically.
Insights
Olomorasib, a next-generation KRASG12C inhibitor, shows potent anti-tumor activity and overcomes resistance mechanisms. It demonstrates efficacy alone and with immunotherapy, offering new hope for KRASG12C-mutant cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- First-generation KRASG12C inhibitors face challenges including drug resistance, poor tolerability, and limited efficacy in combination with immunotherapy.
- KRASG12C mutations are key drivers in various cancers, necessitating novel therapeutic strategies.
Purpose of the Study:
- To introduce olomorasib, a next-generation inhibitor targeting KRASG12C with enhanced potency and selectivity.
- To evaluate the efficacy of olomorasib as a monotherapy and in combination with immune checkpoint inhibitors in preclinical models.
- To assess olomorasib's activity against KRASG12C with common resistance mutations.
Main Methods:
- In vitro and in vivo studies using KRASG12C-mutant cancer models.
- Assessment of RAS activity and pERK signaling pathways.
- Evaluation of anti-tumor efficacy in monotherapy and combination treatment arms.
- Analysis of olomorasib binding affinity in the presence of resistance mutations.
Main Results:
- Olomorasib demonstrated nanomolar potency and selectivity, effectively reducing RAS activity and pERK levels.
- Significant tumor growth inhibition was observed in both in vitro and in vivo models.
- Combination therapy with immune checkpoint inhibitors showed superior anti-tumor activity compared to monotherapy.
- Olomorasib maintained tight binding to KRASG12C even with secondary resistance mutations.
Conclusions:
- Olomorasib represents a promising next-generation KRASG12C inhibitor with potential to overcome existing resistance mechanisms.
- Its efficacy as monotherapy or in combination with immunotherapy warrants further clinical investigation for KRASG12C-mutant cancers.
- Olomorasib may offer a viable treatment option for patients resistant to current therapies.
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