2254P - Persisting RAS addiction: A therapeutic vulnerability in the context of KRAS G12C inhibitor resistance

Background

KRAS is the most frequently mutated oncogene in NSCLC, affecting ∼30% of adenocarcinomas. Resistance to novel KRAS G12C inhibitor monotherapies is inevitable and early data with inactive-state selective inhibitors suggest there are a diverse range of resistance mechanisms.

Methods

A panel of G12C mutant NSCLC cell lines (H358, H23, HCC 1171, H1792, H2122) were cultured with an inactive state selective G12C inhibitor for over 9 months and resistant subclones generated. A multi-omic approach combining genomic, bulk RNA-seq, scRNA-seq and proteomic analyses was used to characterise these resistant populations, with the aim of identifying common resistance mechanisms and potential therapeutic vulnerabilities. In parallel, a PDX has been generated at the point of resistance to a G12C inhibitor, seeking to validate mechanistic insights.

Results

In resistant cell lines, there were varied morphological changes demonstrating both epithelial-mesenchymal-transition (EMT) and mesenchymal-epithelial-transition (MET). Bulk RNA-seq of two cell lines did not reveal common mechanisms of resistance. Further proteomic analysis suggests that there are a diverse range of resistance mechanisms present amongst the resistant populations. To better understand the transition to resistance, scRNA-seq of H1792 cells at different time points was performed, with different transcriptomic states identified. Work is ongoing to explore whether these states confer different sensitivities to G12C inhibition, and whether trajectory inference can predict a path to resistance. Analysis of a PDX has shown that it is a poorly differentiated adenocarcinoma of solid subtype, with further work exploring if this represents a histological transformation from pre-treatment samples. Therapeutic vulnerabilities to the resistant cell line panel were identified, with 5 cell lines remaining sensitive to active state selective RAS inhibitors.

Conclusions

Resistance to inactive state selective KRAS G12C inhibitors is heterogeneous but resistant populations remain sensitive to RAS targeted therapies. These results suggest that KRAS mutant cell lines remain addicted to oncogenic KRAS in the setting of resistance.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Revolution Medicines.

Disclosure

C.R. Lindsay: Financial Interests, Institutional, Advisory Role: Amgen; Financial Interests, Institutional, Research Funding: Revolution Medicines. All other authors have declared no conflicts of interest.