Phosphoinositide kinases in cancer: from molecular mechanisms to therapeutic opportunities

Phosphoinositide kinases, extending beyond the well-known phosphoinositide 3-kinase (PI3K), are key players in the dynamic and site-specific phosphorylation of lipid phosphoinositides. Unlike PI3Ks, phosphatidylinositol 4-kinases (PI4Ks) and phosphatidylinositol phosphate kinases (PIPKs) do not usually exhibit mutational alterations, but mostly show altered expression in tumours, orchestrating a broad spectrum of signalling, metabolic and immune processes, all of which are crucial in the pathogenesis of cancer. Dysregulation of PI4Ks and PIPKs has been associated with various malignancies, which has sparked considerable interest towards their therapeutic targeting. In this Review we summarize the current understanding of the lesser-studied phosphoinositide kinase families, PI4K and PIPK, focusing on their functions and relevance in cancer. In addition, we provide an overview of ongoing efforts driving the preclinical and clinical development of phosphoinositide kinase-targeting molecules.