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Pevonedistat and azacitidine upregulate NOXA (PMAIP1) to increase sensitivity to venetoclax in preclinical models of acute myeloid leukemia
Authors:Dan Cojocari  Brianna N Smith  Julie J. Purkal  Maria P. Arrate  Jason D. Huska  Yu Xiao  Agnieszka Gorska  Leah J. Hogdal  Haley E. Ramsey  Erwin R. Boghaert  Darren C. Phillips  Michael R. Savona
Affiliation:1.Oncology Discovery, AbbVie Inc., North Chicago, IL;2.Department of Pediatrics;3.Medicine;4.Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN;5.Precision Medicine, AbbVie Inc., North Chicago, IL;6.Vanderbilt-Ingram Cancer Center, Nashville, TN;7.Center for Immunobiology, Vanderbilt University School of Medicine, Nashville, TN, USA
Abstract:Dysregulation of apoptotic machinery is one mechanism by which acute myeloid leukemia (AML) acquires a clonal survival advantage. B-cell lymphoma protein-2 (BCL2) overexpression is a common feature in hematologic malignancies. The selective BCL2 inhibitor, venetoclax (VEN) is used in combination with azacitidine (AZA), a DNAmethyltransferase inhibitor (DNMTi), to treat patients with AML. Despite promising response rates to VEN/AZA, resistance to the agent is common. One identified mechanism of resistance is the upregulation of myeloid cell leukemia-1 protein (MCL1). Pevonedistat (PEV), a novel agent that inhibits NEDD8-activating enzyme, and AZA both upregulate NOXA (PMAIP1), a BCL2 family protein that competes with effector molecules at the BH3 binding site of MCL1. We demonstrate that PEV/AZA combination induces NOXA to a greater degree than either PEV or AZA alone, which enhances VEN-mediated apoptosis. Herein, using AML cell lines and primary AML patient samples ex vivo, including in cells with genetic alterations linked to treatment resistance, we demonstrate robust activity of the PEV/VEN/AZA triplet. These findings were corroborated in preclinical systemic engrafted models of AML. Collectively, these results provide rational for combining PEV/VEN/AZA as a novel therapeutic approach in overcoming AML resistance in current therapies.
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