p110 δ PI3K as a therapeutic target of solid tumours

From the time of first characterization of PI3K as a heterodimer made up of a p110 catalytic subunit and a regulatory subunit, a wealth of evidence have placed the class IA PI3Ks at the forefront of drug development for the treatment of various diseases including cancer. The p110 delta isoform was quickly brought at the centre of attention in the field of cancer re-search by the discovery of cancer-specific gain-of-function mutations in PIK3CA gene in a range of human solid tumours. In contrast, p110 delta PI3K was placed into the spotlight of immunity, inflammation and haematologic malignancies because of the preferential expres-sion of this isoform in leucocytes and the rare mutations in PIK3CD gene. The last decade, however, several studies have provided evidence showing that the correlation between the PIK3CA mutations and the response to PI3K inhibition is less clear than originally consid-ered, whereas concurrently an unexpected role of p110 delta PI3K in solid tumours has being emerging. While PIK3CD is mostly non-mutated in cancer, the expression levels of p110 delta protein seem to act as an intrinsic cancer-causing driver in various solid tumours including breast, prostate, colorectal and liver cancer, Merkel -Cell carcinoma, glioblastoma and neu-robalstoma. Furthermore, p110 delta selective inhibitors are being studied as potential single agent treatments or as combination partners in attempt to improve cancer immunotherapy, with both strategies to shown great promise for the treatment of several solid tumours. In this review, we discuss the evidence implicating the p110 delta PI3K in human solid tumours, their impact on the current state of the field and the potential of using p110 delta-selective inhibitors as monotherapy or combined therapy in different cancer contexts.