Pitavastatin counteracts venetoclax resistance mechanisms including TP53 mutation in acute myeloid leukemia.
13 affiliations
- 1Department of Molecular Biology & Biochemistry, University of California Irvine, Irvine, CA.
- 2The Ohio State University Wexner Medical Center, Columbus, OH.
- 3Division of Hematology & Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA.
- 4Division of Hematology & Oncology, College of Medicine, University of Cincinnati, Cincinnati, OH.
- 5Department of Biological Chemistry, Center for Epigenetics and Metabolism, University of California Irvine, Irvine, CA.
- 6Department of Chemistry, University of California Irvine, Irvine, CA.
- 7Biostatistics Shared Resource, University of California Irvine Chao Family Comprehensive Cancer Center, Orange, CA.
- 8Department of Epidemiology and Biostatistics, University of California Irvine, Irvine, CA.
- 9Department of Pathology & Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA.
- 10Hematology/Oncology Section, VA Long Beach Healthcare System, Long Beach, CA.
- 11Division of Hematology-Oncology, Department of Medicine, University of California Irvine, Irvine, CA.
- 12Department of Pharmacology and Toxicology and Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA.
- 13Albert Einstein College of Medicine, Montefiore Einstein Comprehensive Cancer Center, Bronx, NY.
Abstract
The B-cell lymphoma 2 inhibitor venetoclax has therapeutic activity in several hematological malignancies. In acute myeloid leukemia (AML), venetoclax combined with hypomethylating agents is the standard of care for patients unfit for intensive chemotherapy, but intrinsic and acquired resistance are common. Loss of p53 function is strongly associated with venetoclax resistance, and adding venetoclax to 5-azacitidine provides no overall survival benefit in TP53-mutant AML. Other frequent mechanisms of venetoclax resistance in AML include FLT3 mutations, myeloid cell leukemia 1 (MCL-1) upregulation, and altered mitochondrial metabolism. However, it has been challenging to develop agents that target these mechanisms directly and combinatorially. Here, we report that pitavastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, promotes apoptosis and overcomes several venetoclax resistance mechanisms in human AML cells. At clinically achievable concentrations, pitavastatin treatment has potent cytotoxic activity in cells with mutations in TP53 or FLT3, including primary cells resistant to venetoclax and 5-azacitidine. The apoptotic mechanism involves p53-independent PUMA upregulation and reduced MCL-1 expression. Pitavastatin also suppresses mitochondrial gene expression, oxidative metabolism, and MYC/E2F-driven transcription. These results provide a mechanistic rationale for clinical trials adding pitavastatin to AML regimens to prevent or overcome venetoclax resistance with TP53 mutations and other high-risk features.
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BibTeX
@article{buono2026pitavastatin,
title = {{Pitavastatin counteracts venetoclax resistance mechanisms including TP53 mutation in acute myeloid leukemia.}},
author = {Roberta Buono and Dennis Juarez and Madhuri Paul and Sarah J Skuli and Ian B Wong and Ishita Tarnekar and Zhili Ying and Izabelle Marie F Le and Wen-Pin Chen and Min Zhang and Gerald Wertheim and A'ishah Bakayoko and Marisa Kruidenier and Dequina A Nicholas and Pankaj Gupta and Said M Sebti and Marina Konopleva and Angela G Fleischman and Cholsoon Jang and Martin Carroll and David A Fruman},
journal = {Blood neoplasia},
year = {2026},
month = aug,
doi = {10.1016/j.bneo.2026.100296},
url = {https://europepmc.org/article/MED/42893198},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Pitavastatin counteracts venetoclax resistance mechanisms including TP53 mutation in acute myeloid leukemia.
AU - Roberta Buono
AU - Dennis Juarez
AU - Madhuri Paul
AU - Sarah J Skuli
AU - Ian B Wong
AU - Ishita Tarnekar
AU - Zhili Ying
AU - Izabelle Marie F Le
AU - Wen-Pin Chen
AU - Min Zhang
AU - Gerald Wertheim
AU - A'ishah Bakayoko
AU - Marisa Kruidenier
AU - Dequina A Nicholas
AU - Pankaj Gupta
AU - Said M Sebti
AU - Marina Konopleva
AU - Angela G Fleischman
AU - Cholsoon Jang
AU - Martin Carroll
AU - David A Fruman
PY - 2026
DA - 2026/08/28
JO - Blood neoplasia
DO - 10.1016/j.bneo.2026.100296
UR - https://europepmc.org/article/MED/42893198
AB - The B-cell lymphoma 2 inhibitor venetoclax has therapeutic activity in several hematological malignancies. In acute myeloid leukemia (AML), venetoclax combined with hypomethylating agents is the standard of care for patients unfit for intensive chemotherapy, but intrinsic and acquired resistance are common. Loss of p53 function is strongly associated with venetoclax resistance, and adding venetoclax to 5-azacitidine provides no overall survival benefit in TP53-mutant AML. Other frequent mechanisms of venetoclax resistance in AML include FLT3 mutations, myeloid cell leukemia 1 (MCL-1) upregulation, and altered mitochondrial metabolism. However, it has been challenging to develop agents that target these mechanisms directly and combinatorially. Here, we report that pitavastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, promotes apoptosis and overcomes several venetoclax resistance mechanisms in human AML cells. At clinically achievable concentrations, pitavastatin treatment has potent cytotoxic activity in cells with mutations in TP53 or FLT3, including primary cells resistant to venetoclax and 5-azacitidine. The apoptotic mechanism involves p53-independent PUMA upregulation and reduced MCL-1 expression. Pitavastatin also suppresses mitochondrial gene expression, oxidative metabolism, and MYC/E2F-driven transcription. These results provide a mechanistic rationale for clinical trials adding pitavastatin to AML regimens to prevent or overcome venetoclax resistance with TP53 mutations and other high-risk features.
SN - 2950-3280
ER -