Expanding role of PI5P4Ks in cancer: A promising druggable target

Abstract

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 nextin-line treatment for multiple cancer subtypes.

PIP4K2B is a mechanosensor and induces heterochromatin-driven nuclear softening through UHRF1

“…Whether they couple mechanosensing and the control of gene expression is not known. Phosphatidyl Inositol 5-Phosphate 4 Kinases (PI5P4K/PIP4K) are lipid kinases able to phosphorylate PtdIns5P to generate small pools of PtdIns(4,5)P2 compartmentalized at specific cell organelles (10,11). Three isoforms of PIP4K exist in mammalian cells, PIP4K2A, 2B and 2C, mainly localizing in the cytoplasm, nucleus and endomembrane compartments respectively (12)(13)(14)(15).…”

“…Three isoforms of PIP4K exist in mammalian cells, PIP4K2A, 2B and 2C, mainly localizing in the cytoplasm, nucleus and endomembrane compartments respectively (12)(13)(14)(15). Deregulations of these lipid phosphotransferases have been reported in different human cancers (11,16,17). Among the three isoforms, PIP4K2B controls and removes PtdIns5P in the nuclear compartment, impacting on the expression of DNA-damage related genes, chromatin remodeling and protein-histone binding (7)(8)(9).…”

The PIP4K2 inhibitor THZ-P1-2 exhibits antileukemia activity by disruption of mitochondrial homeostasis and autophagy

“…Under physiological conditions, PI-4,5-P 2 -mediated signaling is implicated in many cellular processes, including proliferation, survival, glucose uptake, and cytoskeletal organization, which have been reported to be deregulated in breast cancer, acute leukemias, glioblastoma, and soft tissue sarcomas [ 13 , 18 ]. Cancer genomic and transcriptomic landscape studies have revealed that PIP4K2-related genes are usually not mutated, but their expression is frequently altered [ 13 ]. In ALL, single nucleotide polymorphisms (SNPs) in the regulatory regions of the PIP4K2A gene are associated with increased mRNA levels and risk of disease development [ 19 , 20 ].…”

The PIP4K2 inhibitor THZ-P1-2 exhibits antileukemia activity by disruption of mitochondrial homeostasis and autophagy

“…The family of phosphatidylinositol-5-phosphate 4-kinase type 2 proteins (PIP4K2s) comprises three lipid kinase members (PIP4K2A, PIP4K2B, and PIP4K2C) that phosphorylate the phosphatidylinositol (PI)5P at position four of the inositol ring, generating PI-4,5-P 2 [13]. Furthermore, these enzymes have been associated with the local and specialized generation of PI-4,5-P2 pools in intracellular membranes, being critical for the functionality of endosomes, autophagosomes, lysosomes, and peroxisomes [14,15,16,17].…”

“…Under physiological conditions, PI-4,5-P 2 -mediated signaling is implicated in many cellular processes, including proliferation, survival, glucose uptake, and cytoskeletal organization, which have been reported to be deregulated in breast cancer, acute leukemias, glioblastoma, and soft tissue sarcomas [13,18]. Cancer genomic and transcriptomic landscape studies reveal that PIP4K2-related genes are usually not mutated, but that their expression is frequently altered [13]. In ALL, single nucleotide polymorphisms (SNPs) in regulatory regions of the PIP4K2A gene were associated with increased mRNA levels and risk of disease development [19,20].…”