2022 World Conference on Lung Cancer (ePosters)-EP08.02-079. The Use of Lung Adenocarcinoma Patient-Derived Xenografts and Organoids to Study GDP-KRAS G12C Inhibitor Resistance

EP08.02-079. The Use of Lung Adenocarcinoma Patient-Derived Xenografts and Organoids to Study GDP-KRAS G12C Inhibitor Resistance

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This document discusses the use of lung adenocarcinoma patient-derived xenografts (PDX) and organoids to study resistance to GDP-KRASG12C inhibitors. The study focuses on the potency and selectivity of AZD4625, a novel inhibitor, in treating KRASG12C mutations found in 13% of lung adenocarcinoma cases. The efficacy of AZD4625 was evaluated through cell line viability assays and pharmacokinetic studies in MIA PaCa-2 cells. <br /><br />PDX mouse models and organoids were used to assess the response rate of AZD4625. It was observed that tumor regression occurred at a similar rate as in clinical trials. Long-term KRASG12C LUAD organoids exhibited sensitivity to AZD4625, even after a drug holiday, suggesting the presence of drug-tolerant cell populations. <br /><br />The study also examined acquired resistance mechanisms to KRASG12C inhibitors. A model 194 and other PDX models were used for this purpose. The results of the study indicate that AZD4625 is a promising candidate for studying resistance to G12Ci inhibitors. <br /><br />The research was funded by AstraZeneca, CIHR, Princess Margaret Cancer Foundation, University of Toronto School of Graduate Studies, and the Office of Research Trainees Conference Participation Award. The document includes contact information for further inquiries. <br /><br />Overall, this study demonstrates how PDX and organoid platforms can be used to study resistance to KRASG12C inhibitors and provides insights into the efficacy of AZD4625 in treating lung adenocarcinoma patients with KRASG12C mutations. Future directions include further exploration of resistance mechanisms and potential therapeutic strategies.

Asset Subtitle

Joshua Rosen

Meta Tag

Speaker Joshua Rosen

Topic Metastatic Non-small Cell Lung Cancer - Molecular Targeted Treatments

Keywords

lung adenocarcinoma

patient-derived xenografts

PDX

organoids

resistance

GDP-KRASG12C inhibitors

AZD4625

KRASG12C mutations

efficacy

cell line viability assays