Investigating the effects of avitinib in non-small cell lung cancer

Abstract

Background: Lung cancer is a prevalent global health issue, with an estimated 1.8 million deaths in 2020. It is categorized into small-cell (SCLC) and non-small-cell (NSCLC) lung cancer, with the latter being the most common subtype. A pathway often dysregulated in many cancers is the PI3K/Akt/mTOR pathway, which is primarily activated via tyrosine kinase receptors (RTKs), promoting several cell survival properties including cell growth and proliferation. A subfamily of the RTKs, EGFR, is commonly mutated in NSCLC, causing pathways hyperactivation and leading to oncogenic abnormalities. EGFR variants have been common therapeutic targets over recent years. Several generations of Tyrosine kinase inhibitors (TKIs) have been developed to target RTKs, hence blocking downstream signalling pathways. However, the initial efficacy of EGFR-TKIs began to dimmish due to acquired resistance, namely due to EGFR T790M and L858R substitutions. Avitinib, a third generation EGFR-TKI, has been developed to effectively inhibit EGFR variants, particularly those harbouring the T790M mutation. Aims: The aim of this study is to evaluate the effectiveness of avitinib on two adenocarcinoma NSCLC cell lines, A549 (wild-type EGFR) and H1975 (T790M and L858R mutant EGFR), in decreasing cell viability and proliferation, with the goal of achieving at least a 30% loss of cell viability loss, contributing to the development of more effective treatment options. Methods: Cell viability assays were carried out on the two cell lines, A549 and H1975, testing five different concentrations of avitinib at three time points: 24 hours, 48 hours and 72 hours. This was followed by migration assays to study the effects of four concentrations of avitinib over a period of 96 hours, in order to assess changes in cellular metastatic potential. Results: Avitinib treatment exhibited a concentration-dependant decrease, in cell viability especially at the higher drug concentrations. Additionally, avitinib treatment led to a decrease in cell motility and migration, indicating a concentration-dependant response with sustained impact on cell migration. Conclusion: These results are therefore indicative that avitinib is a potentially ideal small molecule which could be combined with two antisense oligonucleotides targeting HSP27 and TCTP, a study which is currently being conducted at the Department of Clinical Pharmacology and Therapeutics by the Lung Cancer Research Malta group.