Inhibition of <scp>CDK</scp> 9 enhances <scp>AML</scp> cell death induced by combined venetoclax and azacitidine
Relapsed/refractory (R/R) disease is a major hurdle to long-term survival of acute myeloid leukemia (AML) patients treated with intensive cytarabine (AraC)-based chemotherapy. R/R AML salvage treatment with venetoclax (VEN) + azacitidine (AZA) results in overall response rates between 20% and 60%, and responses are not durable, highlighting the need for new therapies. Here, we report elevated mTORC1 signaling in AraC-resistant AML cell lines, primary AML patient samples, and patient-derived xenograft (PDX) AML cells derived from patients at relapse postchemotherapy. The CDK9 inhibitor AZD4573 suppresses mTORC1 signaling and downregulates c-MYC and MCL-1, inducing AraC-resistant AML cell death. AZD4573 in combination with VEN + AZA significantly increases AML cell death compared to any of the two-drug combinations and suppresses AML progenitor cells but spares normal hematopoietic progenitor cells. The efficacy of this triple combination remains even with a 10-fold reduction of VEN concentration. The roles of MCL-1 and c-MYC in the three-drug combination were confirmed by knockdown. This study demonstrates that AZD4573 enhances the activity of VEN + AZA against AraC-resistant AML by downregulating c-MYC and MCL-1 and to a lesser extent cellular respiration.
Authors
- Jeffrey W. Taub (ORCID: https://orcid.org/0000-0003-2228-3235)
- Asfar S. Azmi (ORCID: https://orcid.org/0000-0003-1178-9505)
- Jay Yang (ORCID: https://orcid.org/0000-0003-0790-7951)
- Sijana H. Dzinic (ORCID: https://orcid.org/0009-0000-7543-694X)
- Avanti Gupte (ORCID: https://orcid.org/0000-0002-3235-6111)
- Julie L. Boerner (ORCID: https://orcid.org/0000-0003-1711-4998)
- Maik Hüttemann (ORCID: https://orcid.org/0000-0001-6310-7081)
- Kathryn White
- Holly Edwards
- Shuangshuang Wu (ORCID: https://orcid.org/0000-0002-9526-7976)
- Lisa Polin (ORCID: https://orcid.org/0000-0002-9189-055X)
- Juiwanna Kushner (ORCID: https://orcid.org/0009-0006-9880-8703)
- Jenna Thibodeau
- Shuang Liu (ORCID: https://orcid.org/0000-0001-6306-6929)
- Guan Wang (ORCID: https://orcid.org/0000-0002-7432-7933)
- Yue Wang (ORCID: https://orcid.org/0000-0003-4960-2208)
- Yubin Ge (ORCID: https://orcid.org/0000-0002-8748-716X)
- Jinli Yang
- Jianlei Zhao
Institutions
- Central Michigan University (US)
- Wayne State University (US)
- Jilin University (CN)
- The Barbara Ann Karmanos Cancer Institute (US)
- First Hospital of Jilin University (CN)
- Changchun Children's Hospital (CN)
- Children's Hospital of Michigan (US)
- Ministry of Education (KN)
Publication Details
- Journal
- Molecular Oncology
- Published
- 2025-09-16
- DOI
- https://doi.org/10.1002/1878-0261.70124
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Wayne State University
- Barbara Ann Karmanos Cancer Institute
- Children's Hospital of Michigan
- National Institutes of Health
- H2020 European Research Council