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 next-in-line treatment for multiple cancer subtypes.

Keywords: PI-4,5-P2; PI-5-P; PI5P4K inhibitors; PI5P4Ks (PIP4K); cancer; cellular energetics; lipid kinase; metabolic dependency; p53; phosphoinositides.

Figure 1.. Domain organization of PI5P4Ks.

The schematic representation illustrates the similarity between the three isoforms and depicts the dimerization and kinase domain. It also includes the phosphorylation sites on the isoforms for p38 MAP kinase and mTORC1.

Figure 2.. Comparative overview of PI5P4K isoform expression in multiple cancers.

The heat map is organized based on the difference in median expression between the tumor samples (TCGA datasets) and the corresponding normal tissue samples (from GTEx and TCGA datasets[38]) and the cancer types are ranked based on PIP4K2A expression, going from cancers in which it is most upregulated to the ones it is most downregulated. Cancers highlighted in this review are LAML (Acute Myeloid Leukemia), SARC (Sarcoma), BRCA (Breast invasive carcinoma) and GBM (Glioblastoma multiforme).

Figure 3.. Multipronged effect of pharmacological targeting of PI5P4Ks in the fight against cancer.

PI5P4Ks perform a central role in influencing multiple cancer hallmarks due to its dual role in cell intrinsic pathways as well as in modulation of the immune environment. PI5P4Ks contribute to the classic hallmark of evading cell-death pathways since targeting them selectively decreases survival of cancer cells. PI5P4Ks potentially regulates specialized phosphoinositide pools in subcellular organelles and modulates the dynamic contacts between organelles, exerting a far-reaching impact on cellular energetics as demonstrated by disruption of autophagy, cholesterol trafficking, ROS homeostasis and efficient peroxisomal-mitochondrial cross talk with the manipulation of the kinases. Several of the above-described functional implications arise as a result of alteration in signaling of mTOR, PI3K-Akt and AMPK networks, all of which have been crucial clinical targets for cancer treatment modalities. PI5P4Ks extend their relevance in tumor biology beyond the boundaries of the cells and into the microenvironment by selectively affecting the activity of the T_regs, allowing for the PI5P4K inhibitors to act as a combination of chemo- and immunotherapy.