Synergistic induction of cell death in haematological malignancies by combined phosphoinositide-3-kinase and BET bromodomain inhibition.

Abstract

There has been a marked increase in the development of targeted therapies for the treatment of malignant disease. Responses may be compromised by the presence of pre-existing or treatment-induced resistance mechanisms. The phosphoinositide- 3-kinase (PI3K) pathway has been a major focus of drug development due to its function as a key regulator of cell growth and survival. PI3Ks may be dysregulated by mechanisms including mutations of the negative regulator phosphatase and tensin homologue (PTEN), of regulatory and catalytic subunits and of upstream regulators, such as tyrosine kinases and the RAS family (Fruman & Rommel, 2014). Key targets of PI3K include the serine/threonine kinase AKT and the mechanistic target of rapamycin (MTOR) pathway.