Abstract
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.
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Acknowledgements
We extend our gratitude to the Bioinformatics core at SBPMDI (NCI P30 CA 030199) for the data analysis of Figs. 2 and 3 and Box 1. B.M.E. is supported by the NCI (R01 CA237536), NIGMS (R01 GM143583) and ACS (RSG-20-064-01-TBE). A.L. is supported by the ACS postdoctoral fellowship (PF-24-1318560-01-CDP). The authors are also grateful to the Emerling lab for valuable discussions and suggestions for the manuscript.
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A.L., G.K.A. and B.M.E. wrote, researched data for the article and contributed substantially to discussion of the content. R.M. conducted the bioinformatics analysis for the figures. All authors reviewed and/or edited the manuscript before submission.
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Nature Reviews Cancer thanks Richard Anderson, Nullin Divecha, Volker Haucke and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Broad Single Cell portal: https://singlecell.broadinstitute.org/single_cell/study/SCP1039/a-single-cell-and-spatially-resolved-atlas-of-human-breast-cancers#study-download
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LinkedOmics: https://www.linkedomics.org/data_download/CPTAC-PDAC/
The Cancer Genome Atlas Program (TCGA): https://www.cancer.gov/ccg/research/genome-sequencing/tcga
Glossary
- Autophagic flux
-
A measure of the rate of autophagic degradation, from autophagosome formation and maturation to fusion with lysosomes and the subsequent degradation of their contents.
- Ciliogenesis
-
A process by which cilia, microtubule-based organelles involved in cell motility and signalling, are assembled and extended from the basal body on the surface of eukaryotic cells.
- Circular RNAs
-
Single-stranded RNA molecules that form a covalently closed loop that lacks free 5′ and 3′ ends, which act as transcriptional modulators, microRNA and protein sponges, protein decoys and stabilizers, scaffolds for protein complexes and, in some cases, as protein templates.
- Cytosolic DNA-sensing pathway
-
A cellular defence mechanism that detects foreign DNA derived from invading viruses and bacteria or mislocalized self-DNA in the cytoplasm and mediates a protective immune response through signalling pathways such as cGAS–STING.
- Degrader
-
A bifunctional small molecule that binds a target protein and recruits an E3 ubiquitin ligase, facilitating polyubiquitination and subsequent proteasomal degradation of the target protein.
- Endosomal sorting
-
A process by which cargo is trafficked from endosomes to other organelles, such as lysosomes for degradation, the trans-Golgi network for redistribution to other subcellular locations, or the plasma membrane for recycling.
- Immune checkpoint protein
-
A regulatory protein expressed by immune cells that modulates immune responses to prevent excessive inflammatory reactions that could damage healthy cells. Some cancer cells exploit immune checkpoint proteins to evade immune recognition and killing by suppressing antitumour immune responses.
- Immune synapse
-
A specialized contact area between a lymphocyte (T cell, B cell or natural killer cell) and a target cell or antigen-presenting cell that allows efficient signalling, cell–cell communication and directed protein secretion.
- Invadopodia
-
Specialized actin-rich cellular protrusions that drive the proteolytic degradation of the extracellular matrix, allowing cancer cells to invade surrounding tissues.
- Lamellipodia
-
Specialized actin-rich cellular protrusions at the leading edge of motile cells that drive movement through actin filament polymerization.
- Luminal A breast cancer subtype
-
A molecular subtype of breast cancer that is oestrogen and progesterone receptor positive, human epidermal growth factor receptor 2 negative, and is characterized by a low proliferative index and favourable prognosis and lower risk of recurrence compared with other subtypes.
- Macropinocytosis
-
A unique form of endocytosis characterized by the non-selective uptake of extracellular fluid, solute molecules and membrane in large vesicles known as macropinosomes.
- Multivesicular endosomes
-
Intracellular organelles characterized by the presence of intraluminal vesicles formed by invagination of the limiting endosomal membrane that function as an intermediate compartment in the endosome–lysosome pathway.
- Palmitoylation
-
A post-translational modification in which palmitic acid, a 16-carbon saturated fatty acid, is covalently attached to specific residues of proteins, influencing their localization, stability and function.
- Phosphoinositides
-
Membrane-associated lipid signalling molecules derived from the phosphorylation of phosphatidylinositol that serve as docking sites for proteins involved in essential cellular processes such as signal transduction, vesicular trafficking and cytoskeletal organization.
- Secretory pathway
-
A cellular process involving a coordinated molecular machinery within the endoplasmic reticulum and Golgi apparatus responsible for the synthesis, folding, post-translational modification, trafficking and delivery of functional secretory proteins to the cell surface and extracellular space.
- Senescence
-
A stable state of cell cycle arrest in response to cellular stress or damage, characterized by cellular remodelling and hypersecretion, in which cells are unable to proliferate despite optimal growth conditions.
- Spastic paraplegia
-
A neurological disorder characterized by progressive muscle tightness and weakness in the lower limbs.
- Trans-Golgi network
-
Major sorting compartment formed by a tubulovesicular network at the trans face of the Golgi apparatus that directs newly synthesized proteins to their appropriate subcellular destinations.
- Warburg effect
-
A metabolic adaptation in which cancer cells preferentially use aerobic glycolysis over oxidative phosphorylation, leading to increased glucose uptake and lactate production even in the presence of oxygen and functioning mitochondria, to support the nutritional requirements of uncontrolled proliferation.
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Llorente, A., Arora, G.K., Murad, R. et al. Phosphoinositide kinases in cancer: from molecular mechanisms to therapeutic opportunities. Nat Rev Cancer 25, 463–487 (2025). https://doi.org/10.1038/s41568-025-00810-1
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DOI: https://doi.org/10.1038/s41568-025-00810-1
