Disruption of aneuploidy and senescence induced by aurora inhibition promotes intrinsic apoptosis in double hit or double expressor diffuse large B-cell lymphomas

Shariful Islam, Wenqing Qi, Carla Morales, Laurence Cooke, Catherine S Perry, Eric - Weterings, Daruka Mahadevan

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Double hit (DH) or double expressor (DE) diffuse large B-cell lymphomas (DLBCL) are aggressive non-Hodgkin's lymphomas (NHL) with translocations and/or overexpressions of MYC and BCL-2, which are difficult to treat. Aurora kinase (AK) inhibition with alisertib in DH/DE-DLBCL induces cell death in 30%, while 70% are aneuploid and senescent cells (AASC), a mitotic escape mechanism contributing to drug resistance. These AASCs elaborated a high metabolic rate by increased AKT/mTOR and ERK/MAPK activity via BTK signaling through the chronic active B-cell receptor (BCR) pathway. Combinations of alisertib þ ibrutinib or alisertib þ ibrutinib þ rituximab significantly reduced AASCs with enhanced intrinsic cell death. Inhibition of AK þ BTK reduced phosphorylation of AKT/mTOR and ERK-1/2, upregulated phospho-H2A-X and Chk-2 (DNA damage), reduced Bcl-6, and decreased Bcl-2 and Bcl-xL and induced apoptosis by PARP cleavage. In a DE-DLBCL SCID mouse xenograft model, ibrutinib alone was inactive, while alisertib þ ibrutinib was additive with a tumor growth inhibition (TGI) rate of 25%. However, TGI for ibrutinib þ rituximab was 50% to 60%. In contrast, triple therapy showed a TGI rate of >90%. Kaplan–Meier survival analysis showed that 67% of mice were alive at day 89 with triple therapy versus 20% with ibrutinib þ rituximab. All treatments were well tolerated with no changes in body weights. A novel triple therapy consisting of alisertib þ ibrutinib þ rituximab inhibits AASCs induced by AK inhibition in DH/DE-DLBCL leading to a significant antiproliferative signal, enhanced intrinsic apoptosis and may be of therapeutic potential in these lymphomas.

Original languageEnglish (US)
Pages (from-to)2083-2093
Number of pages11
JournalMolecular Cancer Therapeutics
Volume16
Issue number10
DOIs
StatePublished - Oct 1 2017

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Lymphoma, Large B-Cell, Diffuse
Aneuploidy
Apoptosis
Aurora Kinases
Cell Death
Growth
Neoplasms
Body Weight Changes
SCID Mice
Therapeutics
Survival Analysis
PCI 32765
Drug Resistance
Heterografts
Non-Hodgkin's Lymphoma
DNA Damage
Lymphoma
B-Lymphocytes
Phosphorylation
MLN 8237

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Disruption of aneuploidy and senescence induced by aurora inhibition promotes intrinsic apoptosis in double hit or double expressor diffuse large B-cell lymphomas. / Islam, Shariful; Qi, Wenqing; Morales, Carla; Cooke, Laurence; Perry, Catherine S; Weterings, Eric -; Mahadevan, Daruka.

In: Molecular Cancer Therapeutics, Vol. 16, No. 10, 01.10.2017, p. 2083-2093.

Research output: Contribution to journalArticle

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abstract = "Double hit (DH) or double expressor (DE) diffuse large B-cell lymphomas (DLBCL) are aggressive non-Hodgkin's lymphomas (NHL) with translocations and/or overexpressions of MYC and BCL-2, which are difficult to treat. Aurora kinase (AK) inhibition with alisertib in DH/DE-DLBCL induces cell death in 30{\%}, while 70{\%} are aneuploid and senescent cells (AASC), a mitotic escape mechanism contributing to drug resistance. These AASCs elaborated a high metabolic rate by increased AKT/mTOR and ERK/MAPK activity via BTK signaling through the chronic active B-cell receptor (BCR) pathway. Combinations of alisertib {\th} ibrutinib or alisertib {\th} ibrutinib {\th} rituximab significantly reduced AASCs with enhanced intrinsic cell death. Inhibition of AK {\th} BTK reduced phosphorylation of AKT/mTOR and ERK-1/2, upregulated phospho-H2A-X and Chk-2 (DNA damage), reduced Bcl-6, and decreased Bcl-2 and Bcl-xL and induced apoptosis by PARP cleavage. In a DE-DLBCL SCID mouse xenograft model, ibrutinib alone was inactive, while alisertib {\th} ibrutinib was additive with a tumor growth inhibition (TGI) rate of 25{\%}. However, TGI for ibrutinib {\th} rituximab was 50{\%} to 60{\%}. In contrast, triple therapy showed a TGI rate of >90{\%}. Kaplan–Meier survival analysis showed that 67{\%} of mice were alive at day 89 with triple therapy versus 20{\%} with ibrutinib {\th} rituximab. All treatments were well tolerated with no changes in body weights. A novel triple therapy consisting of alisertib {\th} ibrutinib {\th} rituximab inhibits AASCs induced by AK inhibition in DH/DE-DLBCL leading to a significant antiproliferative signal, enhanced intrinsic apoptosis and may be of therapeutic potential in these lymphomas.",
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AU - Qi, Wenqing

AU - Morales, Carla

AU - Cooke, Laurence

AU - Perry, Catherine S

AU - Weterings, Eric -

AU - Mahadevan, Daruka

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