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Efficacy and Imaging-Enabled Pharmacodynamic Profiling of KRAS G12C Inhibitors in Xenograft and Genetically
Catherine Lee1, Ziyue Karen Jiang2, Simon Planken3
1Oncology Research and Development, Pfizer Inc., Worldwide Research, Development and Medical, San Diego, California.
Abstract:
KRAS is one of the most commonly mutated oncogenes in lung, colorectal, and pancreatic cancers. Recent clinical trials directly targeting KRAS G12C presented encouraging results for a large population of non-small cell lung cancer (NSCLC), but resistance to treatment is a concern. Continued exploration of new inhibitors and preclinical models is needed to address resistance mechanisms and improve duration of patient responses. To further enable the development of KRAS G12C inhibitors, we present a preclinical framework involving translational, non-invasive imaging modalities (CT and PET) and histopathology in a conventional xenograft model and a novel KRAS G12C knock-in mouse model of NSCLC. We utilized an in-house developed KRAS G12C inhibitor (Compound A) as a tool to demonstrate the value of this framework in studying in vivo pharmacokinetic/pharmacodynamic (PK/PD) relationship and anti-tumor efficacy. We characterized the Kras G12C-driven genetically engineered mouse model (GEMM) and identify tumor growth and signaling differences compared to its Kras G12D-driven counterpart. We also find that Compound A has comparable efficacy to sotorasib in the Kras G12C-driven lung tumors arising in the GEMM, but like observations in the clinic, some tumors inevitably progress on treatment. These findings establish a foundation for evaluating future KRAS G12C inhibitors that is not limited to xenograft studies and can be applied in a translationally relevant mouse model that mirrors human disease progression and resistance.
Insights
Developing new KRAS G12C inhibitors is crucial for non-small cell lung cancer (NSCLC) treatment. This study introduces a preclinical framework to evaluate KRAS G12C inhibitors, revealing insights into resistance mechanisms.
Area of Science:
- Oncology
- Molecular Biology
- Preclinical Research
Background:
- KRAS mutations are prevalent in lung, colorectal, and pancreatic cancers.
- Targeting KRAS G12C shows promise in non-small cell lung cancer (NSCLC), but treatment resistance is a significant challenge.
- Novel preclinical models and inhibitors are needed to overcome resistance and prolong patient response duration.
Purpose of the Study:
- To establish a comprehensive preclinical framework for evaluating KRAS G12C inhibitors.
- To investigate the in vivo pharmacokinetic/pharmacodynamic (PK/PD) relationship and anti-tumor efficacy of a novel KRAS G12C inhibitor (Compound A).
- To characterize a KRAS G12C knock-in mouse model for studying NSCLC progression and resistance.
Main Methods:
- Utilized a novel KRAS G12C knock-in genetically engineered mouse model (GEMM) of NSCLC.
- Employed translational, non-invasive imaging modalities (CT and PET) and histopathology.
- Administered an in-house developed KRAS G12C inhibitor (Compound A) and sotorasib for comparative efficacy studies.
Main Results:
- Characterized distinct tumor growth and signaling in the Kras G12C-driven GEMM compared to its Kras G12D counterpart.
- Demonstrated Compound A's comparable efficacy to sotorasib in Kras G12C-driven lung tumors within the GEMM.
- Observed inevitable tumor progression on treatment, mirroring clinical observations and highlighting resistance mechanisms.
Conclusions:
- The developed preclinical framework, utilizing a GEMM and advanced imaging, effectively supports the evaluation of KRAS G12C inhibitors.
- This translational model is valuable for studying resistance mechanisms and assessing novel KRAS G12C inhibitors beyond xenograft studies.
- Findings provide a foundation for developing strategies to improve treatment duration and overcome resistance in KRAS G12C-mutated NSCLC.
