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蛋白酪氨酸激酶 2b 抑制可逆转 AML 中龛相关对酪氨酸激酶抑制剂的耐药性。

Protein tyrosine kinase 2b inhibition reverts niche-associated resistance to tyrosine kinase inhibitors in AML.

机构信息

Department of Medicine V, Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany.

University of Heidelberg Medical Faculty, Heidelberg, Germany.

出版信息

Leukemia. 2022 Oct;36(10):2418-2429. doi: 10.1038/s41375-022-01687-x. Epub 2022 Sep 2.

DOI:10.1038/s41375-022-01687-x
PMID:36056084
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9522596/
Abstract

FLT3 tyrosine kinase inhibitor (TKI) therapy evolved into a standard therapy in FLT3-mutated AML. TKI resistance, however, develops frequently with poor outcomes. We analyzed acquired TKI resistance in AML cell lines by multilayered proteome analyses. Leupaxin (LPXN), a regulator of cell migration and adhesion, was induced during early resistance development, alongside the tyrosine kinase PTK2B which phosphorylated LPXN. Resistant cells differed in cell adhesion and migration, indicating altered niche interactions. PTK2B and LPXN were highly expressed in leukemic stem cells in FLT3-ITD patients. PTK2B/FAK inhibition abrogated resistance-associated phenotypes, such as enhanced cell migration. Altered pathways in resistant cells, assessed by nascent proteomics, were largely reverted upon PTK2B/FAK inhibition. PTK2B/FAK inhibitors PF-431396 and defactinib synergized with different TKIs or daunorubicin in FLT3-mutated AML. Midostaurin-resistant and AML cells co-cultured with mesenchymal stroma cells responded particularly well to PTK2B/FAK inhibitor addition. Xenograft mouse models showed significant longer time to leukemia symptom-related endpoint upon gilteritinib/defactinib combination treatment in comparison to treatment with either drug alone. Our data suggest that the leupaxin-PTK2B axis plays an important role in acquired TKI resistance in AML. PTK2B/FAK inhibitors act synergistically with currently used therapeutics and may overcome emerging TKI resistance in FLT3-mutated AML at an early timepoint.

摘要

FLT3 酪氨酸激酶抑制剂（TKI）治疗已成为 FLT3 突变 AML 的标准治疗方法。然而，TKI 耐药性经常发生，预后不良。我们通过多层蛋白质组分析分析 AML 细胞系中的获得性 TKI 耐药性。Leupaxin（LPXN）是一种调节细胞迁移和黏附的调节剂，在早期耐药性发展过程中与磷酸化 LPXN 的酪氨酸激酶 PTK2B 一起诱导。耐药细胞在细胞黏附和迁移方面存在差异，表明龛位相互作用发生改变。PTK2B 和 LPXN 在 FLT3-ITD 患者的白血病干细胞中高度表达。PTK2B/FAK 抑制可消除与耐药相关的表型，如增强的细胞迁移。通过新生蛋白质组学评估的耐药细胞中改变的途径，在 PTK2B/FAK 抑制后大部分得到逆转。PTK2B/FAK 抑制剂 PF-431396 和 defactinib 与不同的 TKI 或柔红霉素在 FLT3 突变 AML 中协同作用。多柔比星耐药和 AML 细胞与间充质基质细胞共培养时，对添加 PTK2B/FAK 抑制剂的反应特别好。与单独使用任何一种药物相比，在 gilteritinib/defactinib 联合治疗中，移植瘤小鼠模型的白血病症状相关终点时间显著延长。我们的数据表明，leupaxin-PTK2B 轴在 AML 中获得性 TKI 耐药中起重要作用。PTK2B/FAK 抑制剂与目前使用的治疗药物具有协同作用，并可能在早期克服 FLT3 突变 AML 中出现的 TKI 耐药性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb8f/9522596/d38be5892d3f/41375_2022_1687_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb8f/9522596/91a449996e08/41375_2022_1687_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb8f/9522596/fa8f562adc12/41375_2022_1687_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb8f/9522596/fff1d29d0279/41375_2022_1687_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb8f/9522596/f6706e897799/41375_2022_1687_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb8f/9522596/bb94b3ce8840/41375_2022_1687_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb8f/9522596/d38be5892d3f/41375_2022_1687_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb8f/9522596/91a449996e08/41375_2022_1687_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb8f/9522596/fa8f562adc12/41375_2022_1687_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb8f/9522596/fff1d29d0279/41375_2022_1687_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb8f/9522596/f6706e897799/41375_2022_1687_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb8f/9522596/bb94b3ce8840/41375_2022_1687_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb8f/9522596/d38be5892d3f/41375_2022_1687_Fig6_HTML.jpg

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