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Pevonedistat and azacitidine upregulate NOXA (PMAIP1) to increase sensitivity to venetoclax in preclinical models of acute myeloid leukemia

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 wit...

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Autores principales: Cojocari, Dan, Smith, Brianna N, Purkal, Julie J., Arrate, Maria P., Huska, Jason D., Xiao, Yu, Gorska, Agnieszka, Hogdal, Leah J., Ramsey, Haley E., Boghaert, Erwin R., Phillips, Darren C., Savona, Michael R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Fondazione Ferrata Storti 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8968901/
https://www.ncbi.nlm.nih.gov/pubmed/33853293
http://dx.doi.org/10.3324/haematol.2020.272609
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author Cojocari, Dan
Smith, Brianna N
Purkal, Julie J.
Arrate, Maria P.
Huska, Jason D.
Xiao, Yu
Gorska, Agnieszka
Hogdal, Leah J.
Ramsey, Haley E.
Boghaert, Erwin R.
Phillips, Darren C.
Savona, Michael R.
author_facet Cojocari, Dan
Smith, Brianna N
Purkal, Julie J.
Arrate, Maria P.
Huska, Jason D.
Xiao, Yu
Gorska, Agnieszka
Hogdal, Leah J.
Ramsey, Haley E.
Boghaert, Erwin R.
Phillips, Darren C.
Savona, Michael R.
author_sort Cojocari, Dan
collection PubMed
description 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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spelling pubmed-89689012022-04-11 Pevonedistat and azacitidine upregulate NOXA (PMAIP1) to increase sensitivity to venetoclax in preclinical models of acute myeloid leukemia Cojocari, Dan Smith, Brianna N Purkal, Julie J. Arrate, Maria P. Huska, Jason D. Xiao, Yu Gorska, Agnieszka Hogdal, Leah J. Ramsey, Haley E. Boghaert, Erwin R. Phillips, Darren C. Savona, Michael R. Haematologica Article 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. Fondazione Ferrata Storti 2021-04-15 /pmc/articles/PMC8968901/ /pubmed/33853293 http://dx.doi.org/10.3324/haematol.2020.272609 Text en Copyright© 2022 Ferrata Storti Foundation https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (by-nc 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
spellingShingle Article
Cojocari, Dan
Smith, Brianna N
Purkal, Julie J.
Arrate, Maria P.
Huska, Jason D.
Xiao, Yu
Gorska, Agnieszka
Hogdal, Leah J.
Ramsey, Haley E.
Boghaert, Erwin R.
Phillips, Darren C.
Savona, Michael R.
Pevonedistat and azacitidine upregulate NOXA (PMAIP1) to increase sensitivity to venetoclax in preclinical models of acute myeloid leukemia
title Pevonedistat and azacitidine upregulate NOXA (PMAIP1) to increase sensitivity to venetoclax in preclinical models of acute myeloid leukemia
title_full Pevonedistat and azacitidine upregulate NOXA (PMAIP1) to increase sensitivity to venetoclax in preclinical models of acute myeloid leukemia
title_fullStr Pevonedistat and azacitidine upregulate NOXA (PMAIP1) to increase sensitivity to venetoclax in preclinical models of acute myeloid leukemia
title_full_unstemmed Pevonedistat and azacitidine upregulate NOXA (PMAIP1) to increase sensitivity to venetoclax in preclinical models of acute myeloid leukemia
title_short Pevonedistat and azacitidine upregulate NOXA (PMAIP1) to increase sensitivity to venetoclax in preclinical models of acute myeloid leukemia
title_sort pevonedistat and azacitidine upregulate noxa (pmaip1) to increase sensitivity to venetoclax in preclinical models of acute myeloid leukemia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8968901/
https://www.ncbi.nlm.nih.gov/pubmed/33853293
http://dx.doi.org/10.3324/haematol.2020.272609
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