Expanding role of PI5P4Ks in cancer: A promising druggable target

• Published in: FEBS letters Vol. 596; no. 1; pp. 3 - 16
• Main Authors: Arora, Gurpreet K., Palamiuc, Lavinia, Emerling, Brooke M.
• Format: Journal Article
• Language: English
• Published: England 01-01-2022
• Subjects: Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; cancer; cellular energetics; Humans; lipid kinase; metabolic dependency; Molecular Targeted Therapy; Neoplasms - drug therapy; Neoplasms - enzymology; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; p53; phosphoinositides; Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors; Phosphotransferases (Alcohol Group Acceptor) - genetics; Phosphotransferases (Alcohol Group Acceptor) - metabolism; PI5P4K inhibitors; PI5P4Ks (PIP4K); PI‐4,5‐P2; PI‐5‐P; Signal Transduction - drug effects; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; cellular energetics; lipid kinase; PI-4,5-P2; PI-5-P; cancer; PI5P4Ks (PIP4K); metabolic dependency; phosphoinositides; PI5P4K inhibitors; p53
• ISSN: 0014-5793; 1873-3468; 1873-3468
• DOI: 10.1002/1873-3468.14237

Cancer cells are challenged by a myriad of microenvironmental stresses, and it is their ability to efficiently adapt to the constantly changing nutrient, energy, oxidative, and/or immune landscape that allows them to survive and proliferate. Such adaptations, however, result in distinct vulnerabilities that are attractive therapeutic targets. Phosphatidylinositol 5‐phosphate 4‐kinases (PI5P4Ks) are a family of druggable stress‐regulated phosphoinositide kinases that become conditionally essential as a metabolic adaptation, paving the way to targeting cancer cell dependencies. Further, PI5P4Ks have a synthetic lethal interaction with the tumor suppressor p53, the loss of which is one of the most prevalent genetic drivers of malignant transformation. PI5P4K's emergence as a crucial axis in the expanding landscape of phosphoinositide signaling in cancer has already stimulated the development of specific inhibitors. Thus, a better understanding of the biology of the PI5P4Ks will allow for targeted and effective therapeutic interventions. Here, we attempt to summarize the mounting roles of the PI5P4Ks in cancer, including evidence that targeting them is a therapeutic vulnerability and promising next‐in‐line treatment for multiple cancer subtypes.
Therapeutic targeting of phosphatidylinositol 5‐phosphate 4‐kinases (PI5P4Ks) can impact multiple cancer‐specific survival mechanisms. Indeed, PI5P4Ks are druggable lipid kinases with continuously expanding functions being uncovered in multiple cancer subtypes. Thus, PI5P4K‐focused therapies are an exciting potential strategy to target tumor intrinsic metabolic vulnerabilities as well as extrinsic dependencies on the immune microenvironment.