Characterization of drug tolerant persister cells in KRAS G12C mutated lung cancer cells
Embargo Date
2027-10-07
OA Version
Citation
Abstract
Drug tolerant persister (DTP) cells in cancers have become increasingly important to investigate as it allows clinicians and future scientists to understand the development of drug resistance. In kristen rat sarcoma viral oncogene homolog (KRAS) G12C mutated lung cancer, a non-small cell lung cancer (NSCLC), studies have reported an increase in drug resistance to KRAS G12C inhibitors, sotorasib and adagrasib. Drug resistance makes it harder to treat and allows for further lung cancer progression. Limited studies have provided insight on DTP cells for lung cancer with KRAS G12C mutation. In this study through public dataset single cell RNA-sequence (scRNA-seq), candidate maker genes for DTP cells were identified and investigated. Selected candidate genes (B2M, eEF1A1, SOX4, JUNB, and c-FOS) were based on current studies relating the gene to one or more cancers and its potential carcinogenic effects. Apoptosis-related genes such as MCL1 was additionally investigated due to its major role in emergence of DTP cells. Cell lines (H358, H23, and H2122) were treated with sotorasib or adagrasib to allow for emergence of DTP cells. The collected samples were subjected to qPCR and further evaluated through western blotting techniques. Results demonstrated a synergistic effect for combination therapies of KRAS G12C inhibitors and either AP-1 or MCL1 inhibitors. Thus, providing support on how characterization of drug tolerant persister cells can help with therapeutic advances. However, our results suggest that protein expression of AP-1 proteins may be cell-type specific. The results of this study can be taken as a precedent for future investigations in KRAS G12C cells.
Description
2024