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利用白血病干细胞中对PI3激酶抑制的表观遗传抗性机制

Exploiting an Epigenetic Resistance Mechanism to PI3 Kinase Inhibition in Leukemic Stem Cells.

作者信息

Glushakow-Smith Shira G, Kaur Imit, Sidoli Simone, Hemmati Shayda, Angeles Ellen, Sinclair Taneisha, Chakraborty Samarpana, Battle Aaliyah, Ames Kristina, Narayanagari Swathi-Rao, Hyka Rotila, Soto Mark, Tracy Melissa, Vankudoth Jayaram, Kitamura Seiya, Miles Linde, Steidl Ulrich, Shastri Aditi, Verma Amit, Gritsman Kira

机构信息

Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY.

Department of Medicine, Montefiore Hospital, Bronx, NY.

出版信息

bioRxiv. 2025 Jul 15:2025.07.11.663968. doi: 10.1101/2025.07.11.663968.

DOI:10.1101/2025.07.11.663968
PMID:40791365
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12338508/
Abstract

Acquired non-genetic resistance mechanisms to existing therapies contribute to poor outcomes for acute myeloid leukemia (AML) patients, and inability to target leukemic stem cells (LSCs) can lead to relapse. To overcome these challenges, we tested whether LSCs have dependencies on PI3 kinase (PI3K). We found that LSCs are susceptible to isoform-selective targeting of PI3K and are particularly dependent on the P110 alpha isoform of PI3K. We discovered that PI3K inactivation leads to dynamic changes in EZH2/PRC2 function in leukemic cells, and we uncovered downregulation of EZH2 protein levels as a resistance mechanism in response to PI3K inhibition. We found that PI3K inhibition in AML cells can lead to compensatory upregulation of EZH1, and that EZH1 knockdown can sensitize AML cells to PI3K inhibition. We leveraged this resistance mechanism by combining a PI3K inhibitor with an EZH1/2 dual inhibitor, which successfully overcomes the acquired resistance and leads to sustained targeting of AML cells ex vivo and in murine AML and PDX models in vivo. This study identifies a promising novel therapeutic regimen for targeting LSCs in AML.

摘要

对现有疗法产生的获得性非遗传耐药机制导致急性髓系白血病（AML）患者预后不良，而无法靶向白血病干细胞（LSC）会导致复发。为了克服这些挑战，我们测试了LSC是否依赖于PI3激酶（PI3K）。我们发现LSC对PI3K的亚型选择性靶向敏感，并且特别依赖于PI3K的P110α亚型。我们发现PI3K失活会导致白血病细胞中EZH2/PRC2功能的动态变化，并且我们发现EZH2蛋白水平下调是对PI3K抑制的一种耐药机制。我们发现AML细胞中的PI3K抑制可导致EZH1的代偿性上调，并且EZH1敲低可使AML细胞对PI3K抑制敏感。我们通过将PI3K抑制剂与EZH1/2双重抑制剂联合使用来利用这种耐药机制，该联合用药成功克服了获得性耐药，并在体外以及小鼠AML和PDX体内模型中实现了对AML细胞的持续靶向作用。本研究确定了一种有前景的针对AML中LSC的新型治疗方案。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e571/12338508/5abc4b6467ee/nihpp-2025.07.11.663968v1-f0011.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e571/12338508/76aea4bde38c/nihpp-2025.07.11.663968v1-f0010.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e571/12338508/892577aa1f12/nihpp-2025.07.11.663968v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e571/12338508/3454759342f0/nihpp-2025.07.11.663968v1-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e571/12338508/22192c73a669/nihpp-2025.07.11.663968v1-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e571/12338508/7b5ba69fc9c1/nihpp-2025.07.11.663968v1-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e571/12338508/b59787e7d529/nihpp-2025.07.11.663968v1-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e571/12338508/e25c6b010935/nihpp-2025.07.11.663968v1-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e571/12338508/a3a76039f2e3/nihpp-2025.07.11.663968v1-f0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e571/12338508/76aea4bde38c/nihpp-2025.07.11.663968v1-f0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e571/12338508/5abc4b6467ee/nihpp-2025.07.11.663968v1-f0011.jpg

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本文引用的文献

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Targeting a lineage-specific PI3Kɣ-Akt signaling module in acute myeloid leukemia using a heterobifunctional degrader molecule.靶向急性髓系白血病中谱系特异性 PI3Kγ-Akt 信号模块的杂双功能降解分子。
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