Therapeutic potential of PI3K/Akt/mTOR signalling pathway: Effective combination therapy for cancer

Abstract

Cell signalling mechanism plays a vital role in cell functioning. Imbalance and disregulation between these signals, such as phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin signalling pathway may lead to uncontrolled cell proliferation. Generation of drug resistance is the hurdle in current cancer treatment. Designing an effective combination therapy for inhibition of two or more proteins of a given pathway might help to overcome the drug resistance and side effect related issues in cancer treatment. In this regard, application of computational tools firstly to predict newer combinations against phosphatidylinositol-3-kinase, protein kinase B and mammalian target of rapamycin involved in a single pathway have been proposed. The results obtained using the computational tools were shortlisted based on GlideScore and binding interactions of the drugs to the receptors of the pathway. One of the predicted combinations was further subjected to biological evaluation using the Western blot assay. The experimental results revealed synergistic effects that supported the predictions. The study also provided insights for the application and development of computational tools to predict newer combinations in a given network pharmacology.