Investigating the effectiveness and toxicity of novel lung cancer treatment

Abstract

Background: Globally, lung cancer persists as the leading cause of cancer-related deaths with non-small cell lung cancer exhibiting a 5-year survival rate of only 15%, despite the current advancements of available treatments. The dysregulation and aberrant signalling of the PI3k/Akt/mTOR pathway, together with VEGF interplay is commonly observed as a hallmark of lung cancer initiation and progression. Various mechanisms of cellular adaptation to mono-therapeutic agents have been established making the co-administration of treatment targeting this signal cascade a potent therapeutic approach, optimising clinical outcomes. Furthermore, a shift to holistic translational therapeutics is taken wherein cardiovascular disease persists as the leading cause of long-term morbidity and non-cancer related mortality in cancer survivors, mandating the investigation of possible cardiotoxic molecular mechanisms of the individual agents studied and their combination. Aim: The following research aims to analyse the anticancer efficacy of INK128, a dual mTOR inhibitor, and ramucirumab, an anti-VEGFR2 monoclonal antibody, independently and in combination, in lung adenocarcinoma cells as well as their possible cardiotoxicity on cardiomyocytes. Methods: Following optimization studies, the effect of INK128 and ramucirumab treatment, separately and in combination, was evaluated on A549 cells and H9C2 cardiomyocytes through the use of viability assays and wound healing assays. Results were collected at 24-, 48- and 72-hours post-treatment, showing treatment effects on the viability and migratory potential of both cell lines. Results: Both INK128 and ramucirumab decreased the cell viability of A549 lung adenocarcinoma cells, exhibiting the highest effectiveness at 72 hours and at 24 hours respectively. In combinatory treatment, similar trends to those with INK128 were observed, with dose-responses having an overall higher percentage viability at all timepoints when compared to individual treatment. Neither of the agents appeared to have a significant cardiotoxic effect. A statistical significance was observed in A549 migration when treated with INK128 only, but this was not seen in combinatory treatment when compared to the respective controls. Interestingly, a statistically significant variability in H9C2 viability following treatment with INK128 was observed in wound healing and cell viability assays at 48 hours. This result needs to be investigated further for possible cardiotoxicity at this timepoint. Conclusions: The interplay between the PI3K/Akt/mTOR pathway and VEGF/VEGFR signalling poses an attractive therapeutic target for anticancer treatment. The mode of action of INK128 and ramucirumab targets dysregulated malignant mechanistic pathways at different nodes, and hence their combination poses the rationale of a possible augmentation in cancer therapy efficacy. The aim of using this novel approach is founded upon the objective of improving clinical outcomes through translational medicine, reducing potential side effects by lowering doses of individual therapeutic agents while also administering potent and effective oncotheraputic treatments.