Inhibition of CDK9 enhances AML cell death induced by combined venetoclax and azacitidine

  • Mol Oncol. 2025 Sep 16. doi: 10.1002/1878-0261.70124.
Shuangshuang Wu  1 ,  Jianlei Zhao  2  3 ,  Aaban Asfar Azmi  3 ,  Avanti Gupte  4  5 ,  Jenna Thibodeau  6 ,  Shuang Liu  7 ,  Jinli Yang  7 ,  Guan Wang  7 ,  Holly Edwards  2  3 ,  Lisa A Polin  2  3 ,  Juiwanna Kushner  2  3 ,  Sijana H Dzinic  2  3 ,  Kathryn White  2  3 ,  Julie Boerner  2  3 ,  Maik Hüttemann  6  8 ,  Jay Yang  2  3 ,  Yue Wang  1 ,  Jeffrey W Taub  4  5  6  9 ,  Yubin Ge  2  3  6
Affiliations
  • 1. Department of Pediatric Hematology, Children's Medical Center, The First Hospital of Jilin University, Changchun, China.
  • 2. Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA.
  • 3. Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA.
  • 4. Division of Pediatric Hematology/Oncology, Children's Hospital of Michigan, Detroit, MI, USA.
  • 5. Department of Pediatrics, Central Michigan University College of Medicine, Mt. Pleasant, MI, USA.
  • 6. Cancer Biology Graduate Program, Wayne State University School of Medicine, Detroit, MI, USA.
  • 7. National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, School of Life Sciences, Jilin University, Changchun, China.
  • 8. Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA.
  • 9. Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA.
PMID: 40955793 DOI: 10.1002/1878-0261.70124
Abstract

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.

Keywords
AZD4573; acute myeloid leukemia; azacitidine; venetoclax.
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