Combined venetoclax and alvocidib in acute myeloid leukemia

James Bogenberger, Clifford Whatcott, Nanna Hansen, Devora Delman, Chang Xin Shi, Wontak Kim, Hillary Haws, Katherine Soh, Ye Sol Lee, Peter Peterson, Adam Siddiqui-Jain, Steven Weitman, Alexander Keith Stewart, David Bearss, Ruben Mesa, Steven Warner, Raoul Tibes

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

More effective treatment options for elderly acute myeloid leukemia (AML) patients are needed as only 25-50% of patients respond to standard-of-care therapies, response duration is typically short, and disease progression is inevitable even with some novel therapies and ongoing clinical trials. Anti-apoptotic BCL-2 family inhibitors, such as venetoclax, are promising therapies for AML. Nonetheless, resistance is emerging. We demonstrate that venetoclax combined with cyclin-dependent kinase (CDK) inhibitor alvocidib is potently synergistic in venetoclax-sensitive and -resistant AML models in vitro, ex vivo and in vivo. Alvocidib decreased MCL-1, and/or increased pro-apoptotic proteins such as BIM or NOXA, often synergistically with venetoclax. Over-expression of BCL-XL diminished synergy, while knock-down of BIM almost entirely abrogated synergy, demonstrating that the synergistic interaction between alvocidib and venetoclax is primarily dependent on intrinsic apoptosis. CDK9 inhibition predominantly mediated venetoclax sensitization, while CDK4/6 inhibition with palbociclib did not potentiate venetoclax activity. Combined, venetoclax and alvocidib modulate the balance of BCL-2 family proteins through complementary, yet variable mechanisms favoring apoptosis, highlighting this combination as a promising therapy for AML or high-risk MDS with the capacity to overcome intrinsic apoptosis mechanisms of resistance. These results support clinical testing of combined venetoclax and alvocidib for the treatment of AML and advanced MDS.

Original languageEnglish (US)
Pages (from-to)107206-107222
Number of pages17
JournalOncotarget
Volume8
Issue number63
DOIs
StatePublished - Jan 1 2017

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Keywords

  • Acute myeloid leukemia (AML)
  • Alvocidib/flavopiridol
  • BCL-2
  • Venetoclax/ABT-199

ASJC Scopus subject areas

  • Oncology

Cite this

Bogenberger, J., Whatcott, C., Hansen, N., Delman, D., Shi, C. X., Kim, W., Haws, H., Soh, K., Lee, Y. S., Peterson, P., Siddiqui-Jain, A., Weitman, S., Stewart, A. K., Bearss, D., Mesa, R., Warner, S., & Tibes, R. (2017). Combined venetoclax and alvocidib in acute myeloid leukemia. Oncotarget, 8(63), 107206-107222. https://doi.org/10.18632/oncotarget.22284