The “undruggable” dogma of targeting KRAS has been overturned with the recent development of KRAS inhibitors (KRASi). However, the majority of KRAS-mutant lung cancer patients continue to develop treatment resistance and have poor long-term outcomes. Furthermore, co-occurring mutations are known to have a significant impact on tumour biology and treatment outcomes, with resistance mechanisms linked to specific mutational contexts.
Understanding the molecular mechanisms driving resistance to targeted therapy and immune checkpoint inhibitors provides the opportunity to develop novel therapeutic strategies. This project aims to investigate the genomic and transcriptional heterogeneity of KRAS-mutant lung adenocarcinoma (LUAD) and how this relates to treatment responses.
In collaboration with a multi-disciplinary team, genetically engineered mouse models (GEMMs) of human lung cancer have been generated to facilitate the study of tumour evolution within its normal tissue microenvironment (TME). These models include alterations in TP53, KEAP1 and STK11 - tumour suppressor genes, known to frequently occur with KRAS, enabling us to elucidate how specific co-mutations influence therapeutic response.
We have characterised these KRAS-mutant LUAD GEMMs using RNA-seq (n=≥6 per genotype) and compared them to their human counterparts using publicly available whole-exome and RNA-seq datasets. Common transcriptional patterns were observed between the GEMMs and patient cohorts , and there was evidence for a distinct cell phenotype in the KEAP1 co-mutation context. We provide insights into the functional landscape of these novel GEMMs and demonstrate their suitability to explore the molecular heterogeneity observed in KRAS-mutant LUAD. Using these models, we plan to interrogate the TME and drug resistance to KRASi.