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PI3K? inhibition elicits anti-leukemic effects through Bim-dependent apoptosis.

ABSTRACT: PI3K? plays pivotal roles in the maintenance, proliferation and survival of malignant B-lymphocytes. Although not curative, PI3K? inhibitors (PI3K?i) demonstrate impressive clinical efficacy and, alongside other signaling inhibitors, are revolutionizing the treatment of hematological malignancies. However, only limited in vivo data are available regarding their mechanism of action. With the rising number of novel treatments, the challenge is to identify combinations that deliver curative regimes. A deeper understanding of the molecular mechanism is required to guide these selections. Currently, immunomodulation, inhibition of B-cell receptor signaling, chemokine/cytokine signaling and apoptosis represent potential therapeutic mechanisms for PI3K?i. Here we characterize the molecular mechanisms responsible for PI3K?i-induced apoptosis in an in vivo model of chronic lymphocytic leukemia (CLL). In vitro, PI3K?i-induced substantive apoptosis and disrupted microenvironment-derived signaling in murine (E?-Tcl1) and human (CLL) leukemia cells. Furthermore, PI3K?i imparted significant therapeutic responses in E?-Tcl1-bearing animals and enhanced anti-CD20 monoclonal antibody therapy. Responses correlated with upregulation of the pro-apoptotic BH3-only protein Bim. Accordingly, Bim^-/- E?-Tcl1 Tg leukemias demonstrated resistance to PI3K?i-induced apoptosis were refractory to PI3K?i in vivo and failed to display combination efficacy with anti-CD20 monoclonal antibody therapy. Therefore, Bim-dependent apoptosis represents a key in vivo therapeutic mechanism for PI3K?i, both alone and in combination therapy regimes.

SUBMITTER: Carter MJ

PROVIDER: S-EPMC5467045 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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PI3Kδ inhibition elicits anti-leukemic effects through Bim-dependent apoptosis.

Carter M J MJ Cox K L KL Blakemore S J SJ Turaj A H AH Oldham R J RJ Dahal L N LN Tannheimer S S Forconi F F Packham G G Cragg M S MS

Leukemia 20161115 6

PI3Kδ plays pivotal roles in the maintenance, proliferation and survival of malignant B-lymphocytes. Although not curative, PI3Kδ inhibitors (PI3Kδi) demonstrate impressive clinical efficacy and, alongside other signaling inhibitors, are revolutionizing the treatment of hematological malignancies. However, only limited in vivo data are available regarding their mechanism of action. With the rising number of novel treatments, the challenge is to identify combinations that deliver curative regimes ...[more]

PMID: 27843137

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Project description:Effects of concomitant inhibition of the PI3K/AKT/mTOR pathway and Bcl-2/Bcl-xL (BCL2L1) were examined in human myeloid leukemia cells. Tetracycline-inducible Bcl-2 and Bcl-xL dual knockdown sharply increased PI3K/AKT/mTOR inhibitor lethality. Conversely, inducible knockdown or dominant-negative AKT increased, whereas constitutively active AKT reduced lethality of the Bcl-2/Bcl-xL inhibitor ABT-737. Furthermore, PI3K/mTOR inhibitors (e.g., BEZ235 and PI-103) synergistically increased ABT-737-mediated cell death in multiple leukemia cell lines and reduced colony formation in leukemic, but not normal, CD34+ cells. Notably, increased lethality was observed in four of six primary acute myelogenous leukemia (AML) specimens. Responding, but not nonresponding, samples exhibited basal AKT phosphorylation. PI3K/mTOR inhibitors markedly downregulated Mcl-1 but increased Bim binding to Bcl-2/Bcl-xL; the latter effect was abrogated by ABT-737. Combined treatment also markedly diminished Bax/Bak binding to Mcl-1, Bcl-2, or Bcl-xL. Bax, Bak, or Bim (BCL2L11) knockdown or Mcl-1 overexpression significantly diminished regimen-induced apoptosis. Interestingly, pharmacologic inhibition or short hairpin RNA knockdown of GSK3?/? significantly attenuated Mcl-1 downregulation and decreased apoptosis. In a systemic AML xenograft model, dual tetracycline-inducible knockdown of Bcl-2/Bcl-xL sharply increased BEZ235 antileukemic effects. In a subcutaneous xenograft model, BEZ235 and ABT-737 coadministration significantly diminished tumor growth, downregulated Mcl-1, activated caspases, and prolonged survival. Together, these findings suggest that antileukemic synergism between PI3K/AKT/mTOR inhibitors and BH3 mimetics involves multiple mechanisms, including Mcl-1 downregulation, release of Bim from Bcl-2/Bcl-xL as well as Bak and Bax from Mcl-1/Bcl-2/Bcl-xL, and GSK3?/?, culminating in Bax/Bak activation and apoptosis. They also argue that combining PI3K/AKT/mTOR inhibitors with BH3 mimetics warrants attention in AML, particularly in the setting of basal AKT activation and/or addiction.

Dataset Information

PI3K? inhibition elicits anti-leukemic effects through Bim-dependent apoptosis.

Publications

PI3Kδ inhibition elicits anti-leukemic effects through Bim-dependent apoptosis.

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