Voruciclib, a clinical stage oral CDK9 inhibitor, represses MCL-1 and sensitizes high-risk Diffuse Large B-cell Lymphoma to BCL2 inhibition.

Abstract

Aberrant regulation of BCL-2 family members enables evasion of apoptosis and tumor resistance to chemotherapy. BCL-2 and functionally redundant counterpart, MCL-1, are frequently over-expressed in high-risk diffuse large B-cell lymphoma (DLBCL). While clinical inhibition of BCL-2 has been achieved with the BH3 mimetic venetoclax, anti-tumor efficacy is limited by compensatory induction of MCL-1. Voruciclib, an orally bioavailable clinical stage CDK-selective inhibitor, potently blocks CDK9, the transcriptional regulator of MCL-1. Here, we demonstrate that voruciclib represses MCL-1 protein expression in preclinical models of DLBCL. When combined with venetoclax in vivo, voruciclib leads to model-dependent tumor cell apoptosis and tumor growth inhibition. Strongest responses were observed in two models representing high-risk activated B-cell (ABC) DLBCL, while no response was observed in a third ABC model, and intermediate responses were observed in two models of germinal center B-cell like (GCB) DLBCL. Given the range of responses, we show that CIVO, a multiplexed tumor micro-dosing technology, represents a viable functional precision medicine approach for differentiating responders from non-responders to BCL-2/MCL-1 targeted therapy. These findings suggest that the combination of voruciclib and venetoclax holds promise as a novel, exclusively oral combination therapy for a subset of high-risk DLBCL patients.

• Authors: Joyoti Dey, Thomas L Deckwerth, William S Kerwin, Joseph R Casalini, Angela J Merrell, Marc O Grenley, Connor Burns, Sally H Ditzler, Chantel P Dixon, Emily Beirne, Kate C Gillespie, Edward F Kleinman, Richard A Klinghoffer
• Journal: Scientific reports (Sci Rep) Vol. 7 Issue 1 Pg. 18007 (12 21 2017) ISSN: 2045-2322 [Electronic] England
• PMID: 29269870 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• BCL2 protein, human
• Benzopyrans
• Bridged Bicyclo Compounds, Heterocyclic
• Imino Furanoses
• MCL1 protein, human
• Myeloid Cell Leukemia Sequence 1 Protein
• Proto-Oncogene Proteins c-bcl-2
• Sulfonamides
• venetoclax
• voruciclib

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Benzopyrans (pharmacology, therapeutic use)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology, therapeutic use)
• Cell Line, Tumor
• Drug Synergism
• Gene Expression Regulation (drug effects)
• Humans
• Imino Furanoses (pharmacology, therapeutic use)
• Lymphoma, Large B-Cell, Diffuse (drug therapy, genetics, metabolism, pathology)
• Mice
• Myeloid Cell Leukemia Sequence 1 Protein (genetics, metabolism)
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• Sulfonamides (pharmacology, therapeutic use)