Evaluating dual PI3-kinase and BET-bromodomain inhibitors for the treatment of T-cell lymphoma

PI3-kinase mediates pro-survival signalling in many cancer types and is a bone fide therapeutic target exploited by PI3-kinase inhibitors in the clinic. Resistance to PI3-kinase inhibitors occurs in cancer cells when they redirect pro-survival signalling down compensatory pathways. To do this they exercise transcriptional plasticity mediated by BET-bromodomain containing proteins at the chromatin interface. BET-bromodomain inhibitors themselves are in clinical development as 'epigenetic therapy' for blood cancers. Because of their unique and complementary mechanisms of action, combining PI3-kinase with BET-bromodomain inhibitors conveys synergistic anticancer activity and prevents secondary drug resistance. In collaboration with our medicinal chemistry experts at the Monash Institute of Pharmaceutical Sciences, we have developed and patented chimeric 'dual targeted' PI3K/BET inhibitors (Oh et al, Proc Natl Acad Sci USA 2023; 120: e2306414120) which elicited curative responses in models of aggressive B-cell lymphoma. In this project, we are evaluating the efficacy of our novel dual inhibitor series against the much rarer and more difficult to treat T-cell lymphoma subtypes. Here we will optimise the best inhibitors from our patented series in models of T-cell lymphoma while using CRISPR/Cas9 screening to determine mechanism of resistance to dual inhibitors. We will also explore new kinase/epigenetic target combinations to incorporate into novel chimeric drugs delivering 'synergy in a single molecule'.