The dysregulation and aberrant signaling of the PI3k/Akt/mTOR pathway, together with VEGF interplay, is commonly observed as a hallmark of lung cancer initiation and progression, making this an attractive target in treating non-small cell lung cancer. Simultaneously, inhibiting upstream and downstream effectors within this pathway, may contribute to better clinical outcomes. Being a critical regulator of cell health, the suppression of components in this pathway may however inadvertently negatively impact physiological cellular functioning, especially in the context of cardiotoxicity, which persists as the leading cause of long-term morbidity and non-cancer related mortality in cancer survivors.

This study aimed to investigate the anti-cancer efficacy and possible cardiotoxicity of the direct VEGFR-2 antagonist, ramucirumab and the dual mTOR inhibitor, INK128, separately and in combination, based on a mechanistic hypothesis of pathway co-inhibition. Changes in cell viability were assessed on A549 lung adenocarcinoma cells and H9C2 cardiomyocytes following INK128 and ramucirumab treatment, both separately and in combination.

Both INK128 and ramucirumab monotherapies caused a concentration-dependent decrease in the viability of A549 cells. Results of the combinatory treatment exhibited similar trends to INK128 monotherapy. Treatments did not cause a significant decrease in cardiomyocyte viability overall, pointing towards the treatments’ safety in terms of cardiotoxicity.

Future work will aim to investigate efficacy and toxicity in better biomimetic ex vivo and in vivo models, augmenting translational relevance and clinical safety. These models may be key to translational medicine research, in evaluating novel combinational oncopharmacology and possible toxicities, sustaining hope in better holistically clinical outcomes.