2022 World Conference on Lung Cancer (ePosters)-EP16.03-025. Immunogenomics of Clinical Resistance to KRAS G12C Inhibition

Pdf Summary

This research study focused on understanding the mechanisms of resistance to G12C inhibition, a targeted therapy for lung adenocarcinoma with KRAS G12C mutation. The study analyzed pre- and post-treatment tumor samples from a patient treated with the G12C inhibitor sotorasib. <br /><br />The results showed that post-treatment samples overexpressed oncogenic signatures related to MAPK/ERK, AKT, and mTOR signaling, as well as hallmark pathway signatures related to cellular differentiation, proliferation, angiogenesis, and epithelial-mesenchymal transition. The mutation allele frequency of KRAS G12C decreased in many post-treatment tumor samples, regardless of tumor purity and copy number variation. This was negatively correlated with the expression of several oncogenic and metabolic pathways, suggesting plausible escape mechanisms and diversification of tumor metabolic sources. Phylogenetic analysis indicated the persistence of multiple shared clones from pre- to post-treatment, involving multiple pre-treatment tumors in the development of resistant tumors observed during and post-treatment.<br /><br />Furthermore, the study found that the expression of signatures related to immune cell activation and infiltration was generally decreased in the post-treatment setting. There was limited overlap between pre- and post-treatment tumor T and B-cell repertoires, suggesting remodeling of the tumor immune microenvironment. <br /><br />The research utilized RNA and whole exome sequencing to explore genomic and immunologic mechanisms of therapy resistance. Gene set variation analysis, phylogenetic tree analysis, and correlation analysis were performed to examine the findings. These results contribute to the understanding of resistance mechanisms to G12C inhibition and provide insights that could guide future therapeutic developments. The full methods and data of the study are available for further reference.

Asset Subtitle

Mark Woodcock

Meta Tag

Speaker Mark Woodcock

Topic Tumour Biology and Biomarkers - Molecular Profiling and Targeted Therapies

Keywords

G12C inhibition

lung adenocarcinoma

KRAS G12C mutation

tumor samples

oncogenic signatures

MAPK/ERK signaling

mutation allele frequency

escape mechanisms

immune cell infiltration

therapy resistance