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Review
. 2019 Jan 18;20(2):412.
doi: 10.3390/ijms20020412.

Targeting PI3K Signaling in Acute Lymphoblastic Leukemia

Vanessa Edna Sanchez  1   2 , Cydney Nichols  3 , Hye Na Kim  4 , Eun Ji Gang  2 , Yong-Mi Kim  5
Affiliations
Review

Targeting PI3K Signaling in Acute Lymphoblastic Leukemia

Vanessa Edna Sanchez et al. Int J Mol Sci. .

Abstract

Adhesion of acute lymphoblastic leukemia (ALL) cells to bone marrow stroma cells triggers intracellular signals regulating cell-adhesion-mediated drug resistance (CAM-DR). Stromal cell protection of ALL cells has been shown to require active AKT. In chronic lymphocytic leukemia (CLL), adhesion-mediated activation of the PI3K/AKT pathway is reported. A novel FDA-approved PI3Kδ inhibitor, CAL-101/idelalisib, leads to downregulation of p-AKT and increased apoptosis of CLL cells. Recently, two additional PI3K inhibitors have received FDA approval. As the PI3K/AKT pathway is also implicated in adhesion-mediated survival of ALL cells, PI3K inhibitors have been evaluated preclinically in ALL. However, PI3K inhibition has yet to be approved for clinical use in ALL. Here, we review the role of PI3K in normal hematopoietic cells, and in ALL. We focus on summarizing targeting strategies of PI3K in ALL.

Keywords: PI3K/AKT; PI3Kδ; acute lymphoblastic leukemia (ALL); cell adhesion mediated drug resistance (CAM-DR).

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Phosphoinositide 3-kinases (PI3Ks) regulate cellular processes including cell survival, adhesion, and proliferation. PI3K is activated by receptor tyrosine kinases (RTKs), Integrins, or G-protein coupled receptors (GPCRS) at the surface of the cell. PI3K phosphorylates phosphatidylinositol-diphosphate (PIP2) into phosphatidylinositol triphosphate (PIP3), which in turn activate the serine/threonine kinase AKT regulations survival, adhesion and proliferation. PTEN (phosphatase and tensin homolog deleted from chromosome 10) negatively regulates PI3K signaling. formula image = Activation; ⊥ = Inhibition.
Figure 2
Figure 2
PI3K pathway inhibitors target one or more aspects of PI3K signaling. PKI-587 and BEZ235 are dual PI3K/mTOR inhibitors. ZSTK-474 is a pan-PI3K inhibitor. Idelalisib and PI3K-IN-015 are each targeting PI3Kdelta isoforms. Duvelisib is a dual PI3K gamma/delta inhibitor. SF2535 is a novel PI3Kdelta/BRD4 inhibitor. → = Include formula image = Activation ⊥ = Inhibition.
See this image and copyright information in PMC

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