IBL-202 is synergistic with venetoclax in CLL under in vitro conditions that mimic the tumor microenvironment

Yandong Shen, Kyle Crassini, Narjis Fatima, Michael O’Dwyer, Michael O’Neill, Richard I. Christopherson, Stephen P. Mulligan, O. Giles Best

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1 Citation (Scopus)

Abstract

The B-cell receptor signaling pathway and dysregulation of the Bcl-2 family of proteins play crucial roles in the pathogenesis of chronic lymphocytic leukemia (CLL). Despite significant advances in the treatment of the disease, relapse and drug resistance are not uncommon. In the current study, we investigated the dual PI3/PIM kinase inhibitor IBL-202 in combination with venetoclax as a treatment option for CLL using both primary CLL cells and TP53-deficient OSU-CLL cells generated using the CRISPR-Cas9 system. IBL-202 and venetoclax were highly synergistic against primary CLL cells cocultured with CD40L fibroblasts (combination index [CI], 0.4, at a fractional effect of 0.9) and TP53-knockout (KO) OSU-CLL cells (CI, 0.5, at a fractional effect of 0.9). Synergy between the drugs was consistent, with a significant (P, .05) reduction in the 50% inhibitory concentration for both drugs. IBL-202 and venetoclax in combination induced cell-cycle arrest and slowed the proliferation of both wild-type and TP53-KO cell lines. The drug combination inhibited AKT phosphorylation, reduced expression of Bcl-xL and NF-kB, and increased the Noxa/Mcl-1 ratio. Downregulation of CXCR4 was consistent with inhibition of the SDF-1a–induced migratory capacity of CLL cells. Synergy between IBL-202 and venetoclax against primary CLL cells cultured under conditions that mimic the tumor microenvironment suggests this drug combination may be effective against CLL cells within the lymph nodes and bone marrow. Furthermore, the efficacy of the combination against the TP53-KO OSU-CLL cell line suggests the combination may be a highly effective treatment strategy for high-risk CLL.

Original languageEnglish
Pages (from-to)5093-5106
Number of pages14
JournalBlood Advances
Volume4
Issue number20
DOIs
Publication statusPublished - 21 Oct 2020

Keywords

  • Lymphoid Neoplasia
  • PI3/PIM kinase inhibitor IBL-202
  • venetoclax
  • TP53-deficient CLL cells.
  • chronic lymphocytic leukemia (CLL)

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