Combination of the dual PIM/PI3-kinase inhibitor IBL-202 and venetoclax is effective in diffuse large B-cell lymphoma

Abstract

Current chemoimmunotherapy is unable to cure up to 40% of patients diagnosed with diffuse large B-cell lymphoma (DLBCL). Targeting the mechanisms by which DLBCL evades apoptosis is crucial to overcoming treatment failure in this heterogeneous disease as both current and novel treatments depend on the apoptosis of malignant cells. Despite the common overexpression of BCL-2, venetoclax is ineffective in DLBCL due to MCL-1 co-expression. This is driven by pro-growth PI3-kinase signaling, which is promoted in turn by PIM kinases. In this study, the novel dual-kinase inhibitor, IBL-202, was combined with venetoclax against a panel of DLBCL cell lines that have variable expression of pro-survival proteins. The results support the efficacy of simultaneously targeting inter-related molecules to overcome apoptotic escape in this biologically heterogeneous disease. As venetoclax, pan-PIM-kinase and pan-PI3-kinase inhibitors have, or are currently being studied in clinical trials, it may be rational to consider these drugs in combination for the treatment of DLBCL.

Keywords:

• Lymphoma and Hodgkin disease < neoplasia
• cell cycle and apoptosis
• changes < neoplasia
• drug resistance < neoplasia

Acknowledgements

Prof. Karen Dybkaer (Aalborg University Hospital, Denmark) for the provision of DLBCL cell lines. National Cancer Institute (Bethesda, Maryland, United States of America) for the use of the cell-of-origin classifier, Lymph2Cx. Inflection Biosciences (Blackrock, Dublin, Ireland) for the provision of IBL-202.

Author contributions

GG and GB designed and performed the research, analyzed the data, wrote the paper and approved the submitted and final versions. WS critically revised drafts of the paper, approved the submitted and final versions of the paper.

Disclosure statement

The authors have no conflict of interests to disclose.