Abstract
The landscape of cancer treatment has shifted with the development of molecularly targeted therapies, offering precision in targeting specific pathways. However, the emergence of drug resistance renders these therapies ineffective, resulting in disease progression despite ongoing treatment. As genetic mutations alone cannot fully explain drug resistance, there is a need to explore epigenetic aberrations that provide cancer cells with a dynamic and reversible means to adapt to therapies.
This research investigates the epigenetic mechanisms behind drug resistance in lung cancer, focusing on transcriptomic changes. We aimed to identify the molecular changes that confer resistance by analysing the transcriptomes of lung cancer cells exposed to targeted therapies. Lung adenocarcinoma (LUAD) cell lines with distinct oncogenic driver mutations (EGFR, KRAS, ALK) were cultured and treated with their respective tyrosine kinase inhibitors (TKIs): Osimertinib, Sotorasib, and Crizotinib. These cultures were observed over 3, 7, and 19 days to capture the development of drug resistance. Initial treatment resulted in a significant reduction in cell density; however, even after 19 days of drug exposure, viable cancer cells persisted, with the EGFR-mutant cell line showing near-confluent regrowth.
RNA sequencing of these samples revealed dynamic transcriptomic changes in response to the treatments when compared to untreated controls. Notably, each cell line exhibited unique adaptations to prolonged drug exposure. While the expression patterns across the cell lines appeared largely stochastic, a distinct subset of significant gene expression changes was consistently detected early in treatment and sustained throughout the duration of drug exposure.
This suggests that key shifts associated with drug resistance may be initiated during the early stages of therapy. These findings underscore the complexity of drug resistance, suggesting that epigenetic reprogramming and specific gene expression changes facilitate cancer cell survival despite continuous drug treatment.
The identification of early transcriptomic changes that persist throughout prolonged drug exposure provides valuable insights into the temporal dynamics of resistance development. This project highlights the importance of epigenetic reprogramming as a dynamic and reversible mechanism, underscoring its critical role in drug resistance. By characterizing these early shifts, future treatment strategies may focus on preventing resistance before it becomes fully established, potentially extending the efficacy of targeted therapies.