Depletion of a Putatively Druggable Class of Phosphatidylinositol Kinases Inhibits Growth of p53-Null Tumors

By B. Emerling, J. Hurov, G. Poulogiannis, Kazumi S. Tsukazawa, R. Choo-wing, G. Wulf, Eric L. Bell, Hyeseok Shim, Katja A. Lamia, L. Rameh and 10 more. 2013

190 citations recorded by the source corpus.

SUMMARY Here, we show that a subset of breast cancers express high levels of the type 2 phosphatidylinositol-5-phosphate 4-kinases α and/or β (PI5P4Kα and β) and provide evidence that these kinases are essential for growth in the absence of p53. Knocking down PI5P4Kα and β in a breast cancer cell line bearing an amplification of the gene encoding PI5P4K β and deficient for p53 impaired growth on plastic and in xenografts. This growth phenotype was accompanied by enhanced levels of reactive oxygen species (ROS) leading to senescence. Mice with homozygous deletion of both TP53 and PIP4K2B were not viable, indicating a synthetic lethality for loss of these two genes. Importantly however, PIP4K2A−/−, PIP4K2B+/−, and TP53−/− mice were viable and had a dramatic reduction in tumor formation compared to TP53−/− littermates. These results indicate that inhibitors of PI5P4Ks could be effective in preventing or treating cancers with mutations in TP53.

Subfields: Immunology, Molecular Biology, Oncology

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Citations in the corpus

PIP4Ks Suppress Insulin Signaling through a Catalytic-Independent Mechanism (2018, unknown): “We initially had reservations about the development of such drugs due to the embryonic lethality of germline co-deletion of PIP4K2B and PIP4K2C or PIP4K2A and PIP4K 2B (Emerling et al., 2013; Shim et al., 2016).”
Targeting the PI5P4K lipid kinase family in cancer using covalent inhibitors (2020, background): “…be a dependency in AML and ALL (Jude et al., 2014; RosalesRodríguez, et al., 2016; Urayama et al., 2018) and PIP4K2A−/−, PIP4K2B+/−, TP53−/− mice had a dramatic tumor-free life extension compared to TP53−/− mice, uncovering a potential synthetic lethality of PI5P4K with p53 (Emerling et al., 2013).”
In B cells, phosphatidylinositol 5-phosphate 4-kinase–α synthesizes PI(4,5)P2 to impact mTORC2 and Akt signaling (2016, background): “No Akt phenotype was found in PIP4K2A knockout mice (21), but as far as we are aware, cells of the hematopoietic lineage were not studied there; another study from the same group elegantly showed the tissue variability of gene knockouts, with PIP4K2B knockout mice having enhanced insulininduced Akt ”
Deletion of the gene Pip4k2c, a novel phosphatidylinositol kinase, results in hyperactivation of the immune system (2016, background): “Deletion of Pip4k2b enhances Akt activation but, surprisingly, does not result in enhanced mTORC1 signaling (4, 5).”
A targeted knockdown screen of genes coding for phosphoinositide modulators identifies PIP4K2A as required for acute myeloid leukemia cell proliferation and survival (2014, methodology): “Next, we performed two additional full screens using cell lines representative of other molecular subtypes of AML: Kasumi1 (carrying a t(8;21) translocation, the cytogenetic hallmark of a RUNX1-RUNX1T1 fusion) and U937”
The lipid kinase PI5P4Kβ is an intracellular GTP sensor for metabolism and tumorigenesis (2016, unknown): “PI5P4Ks have been shown to promote tumorigenesis in several types of cancers (Emerling et al., 2013; Jude et al., 2015; Keune et al., 2013; Luoh et al., 2004), raising the possibility that the GTP-sensing activity of PI5P4Kb is involved in its tumorigenic activity.”
Phosphatidylinositol-5-phosphate 4-kinases regulate cellular lipid metabolism by facilitating autophagy (2018, methodology): “Mice deficient in the two most catalytically active PI5P4Ks (Pip4k2a−/−Pip4k2b−/−) develop into normal embryos, but die within 12 hours after birth (Emerling et al., 2013).”