2. Academic Validation
  3. A Temporal PROTAC Cocktail-Mediated Sequential Degradation of AURKA Abrogates Acute Myeloid Leukemia Stem Cells

A Temporal PROTAC Cocktail-Mediated Sequential Degradation of AURKA Abrogates Acute Myeloid Leukemia Stem Cells

  • Adv Sci (Weinh). 2022 Aug;9(22):e2104823. doi: 10.1002/advs.202104823.
Fang Liu 1,  Xuan Wang 1,  Jianli Duan 1,  Zhijie Hou 2,  Zhouming Wu 1,  Lingling Liu 3,  Hanqi Lei 4,  Dan Huang 5,  Yifei Ren 5,  Yue Wang 2,  Xinyan Li 1,  Junxiao Zhuo 1,  Zijian Zhang 1,  Bin He 1,  Min Yan 1,  Huiming Yuan 6,  Lihua Zhang 6,  Jinsong Yan 5,  Shijun Wen 1,  Zifeng Wang 1,  Quentin Liu 1 2 3
Affiliations

Affiliations

  • 1 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.
  • 2 Institute of Cancer Stem Cell, Dalian Medical University, Dalian, 116044, China.
  • 3 Department of Hematology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
  • 4 Department of Urology, Kidney and Urology Center, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518000, China.
  • 5 Department of Hematology, the Second Affiliated Hospital of Dalian Medical University, Dalian, 116027, China.
  • 6 CAS Key Laboratory of Separation Sciences for Analytical Chemistry, National Chromatographic R&A Center, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China.
PMID: 35652200 DOI: 10.1002/advs.202104823
Abstract

AURKA is a potential kinase target in various malignancies. The kinase-independent oncogenic functions partially disclose the inadequate efficacy of the kinase inhibitor in a Phase III clinical trial. Simultaneously targeting the catalytic and noncatalytic functions of AURKA may be a feasible approach. Here, a set of AURKA proteolysis targeting chimeras (PROTACs) are developed. The CRBN-based dAurA383 preferentially degrades the highly abundant mitotic AURKA, while cIAP-based dAurA450 degrades the lowly abundant interphase AURKA in acute myeloid leukemia (AML) cells. The proteomic and transcriptomic analyses indicate that dAurA383 triggers the "mitotic cell cycle" and "stem cell" processes, while dAurA450 inhibits the "MYC/E2F targets" and "stem cell" processes. dAurA383 and dAurA450 are combined as a PROTAC cocktail. The cocktail effectively degrades AURKA, relieves the hook effect, and synergistically inhibits AML stem cells. Furthermore, the PROTAC cocktail induces AML regression in a xenograft mouse model and primary patient blasts. These findings establish the PROTAC cocktail as a promising spatial-temporal drug administration strategy to sequentially eliminate the multifaceted functions of oncoproteins, relieve the hook effect, and prevent Cancer stem cell-mediated drug resistance.

Keywords

Aurora kinase A (AURKA); E3 ubiquitin ligase; PROTAC cocktail; acute myeloid leukemia stem cells.

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