Liu, F; Wang, X; Duan, JL; Hou, ZJ; Wu, ZM; Liu, LL; Lei, HQ; Huang, D; Ren, YF; Wang, Y; Li, XY; Zhuo, JX; Zhang, ZJ; He, B; Yan, M; Yuan, HM; Zhang, LH; Yan, JS; Wen, SJ; Wang, ZF; Liu, QT
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: acute myeloid leukemia stem cells; Aurora kinase A (AURKA); PROTAC cocktail; E3 ubiquitin ligase
The concept of utilizing PROTAC (Proteolysis Targeting Chimeras) cocktails presents a promising avenue for effectively targeting and eliminating acute myeloid leukemia (AML) stem cells, which are notoriously resistant to conventional therapies and responsible for disease relapse. By leveraging the principles of targeted protein degradation, PROTACs are designed to recruit specific proteins of interest for ubiquitination and subsequent proteasomal degradation, offering a novel approach to disrupting key signaling pathways implicated in cancer progression. In the context of AML, where aberrant protein expression drives leukemic stem cell survival and proliferation, PROTAC cocktails can be tailored to simultaneously target multiple essential proteins involved in leukemogenesis, thus enhancing therapeutic efficacy and minimizing the likelihood of resistance development. Furthermore, the temporal dynamics of PROTAC cocktails allow for sustained and selective degradation of target proteins, offering a prolonged therapeutic effect while minimizing off-target effects on normal cells. Additionally, the versatility of PROTAC technology enables the design of cocktails that can overcome heterogeneity within AML stem cell populations, ensuring comprehensive targeting of diverse leukemic clones. As research in PROTAC-based therapies continues to advance, the development of optimized cocktails tailored to the specific molecular profiles of individual patients holds great promise for achieving durable remissions and improving outcomes in AML treatment.
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