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Review
. 2022:436:393-407.
doi: 10.1007/978-3-031-06566-8_17.

PI3K Targeting in Non-solid Cancer

Hye Na Kim  1 , Heather Ogana  1 , Vanessa Sanchez  1 , Cydney Nichols  1 , Yong-Mi Kim  2
Affiliations
Review

PI3K Targeting in Non-solid Cancer

Hye Na Kim et al. Curr Top Microbiol Immunol. 2022.

Abstract

Despite the therapeutic progress, relapse remains a major problem in the treatment of acute lymphoblastic leukemia (ALL). Most leukemia cells that survive chemotherapy are found in the bone marrow (BM), thus resistance to chemotherapy and other treatments may be partially attributed to pro-survival signaling to leukemic cells mediated by leukemia cell-microenvironment interactions. Adhesion of leukemia cells to BM stromal cells may lead to cell adhesion-mediated drug resistance (CAM-DR) mediating intracellular signaling changes that support survival of leukemia cells. In ALL and chronic lymphocytic leukemia (CLL), adhesion-mediated activation of the PI3K/AKT signaling pathway has been shown to be critical in CAM-DR. PI3K targeting inhibitors have been approved for CLL and 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 signaling for normal hematopoietic and leukemia cells and summarize preclinical inhibitors of PI3K in ALL.

Keywords: Acute lymphoblastic leukemia (ALL); Cell adhesion mediated drug resistance (CAM-DR); PI3K/AKT; PI3Kγ; PI3Kδ.

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Conflict of interest statement

Conflicts of Interest The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
The phosphoinositide-3-kinases (PI3Ks) signaling pathway. Stromal cell secretion of chemokines and cytokines activates the PI3K/AKT signaling pathway in leukemia cells. PI3K is activated by G-protein coupled receptors (GPCRs), integrins, receptor tyrosine kinases (RTKs), or B cell receptors. PI3K can phosphorylate phosphatidylinositol-diphosphate (PIP2) into phosphatidylinositol triphosphate (PIP3), which may phosphorylate and activate the serine/threonine kinase AKT. PTEN (phosphatase and tensin homolog deleted from chromosome 10) negatively regulates PI3K signaling.
Fig. 2
Fig. 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 PI3Kδ isoforms. Duvelisib is a dual PI3Kγ/δ inhibitor. Adapted from Sanchez et al. 2019, originally published under CC BY
See this image and copyright information in PMC

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