Combined venetoclax and alvocidib in acute myeloid leukemia
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James Bogenberger1,*, Clifford Whatcott2,*, Nanna Hansen1, Devora Delman1, Chang-Xin Shi1, Wontak Kim2, Hillary Haws2, Katherine Soh2, Ye Sol Lee2, Peter Peterson2, Adam Siddiqui-Jain2, Steven Weitman2, Keith Stewart1, David Bearss2, Ruben Mesa1, Steven Warner2 and Raoul Tibes1,3
1Mayo Clinic, Scottsdale, AZ, USA
2Tolero Pharmaceuticals, Lehi, UT, USA
3NYU School of Medicine, New York, NY, USA
*These authors contributed equally to this work
Raoul Tibes, email: [email protected]
James Bogenberger, email: [email protected]
Keywords: acute myeloid leukemia (AML); alvocidib/flavopiridol; venetoclax/ABT-199; BCL-2
Received: July 22, 2017 Accepted: October 10, 2017 Published: November 03, 2017
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.
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