BTK inhibitor therapy induces peripheral blood lymphocytosis in chronic lymphocytic leukemia (CLL) lasting for several months. It remains unclear whether non-genetic adaptation mechanisms exist, allowing CLL cells' survival during BTK inhibitor-induced lymphocytosis and/or playing a role in therapy resistance. We show that in approximately 70 % of CLL cases, ibrutinib treatment in vivo increases Akt activity above pre-therapy levels within several weeks, leading to compensatory CLL cell survival and a more prominent lymphocytosis on therapy. Ibrutinib-induced Akt phosphorylation (pAktS473) is caused by the upregulation of FoxO1 transcription factor, which induces expression of Rictor, an assembly protein for mTORC2 protein complex that directly phosphorylates Akt at serine 473 (S473). Knock-out or inhibition of FoxO1 or Rictor led to a dramatic decrease in Akt phosphorylation and growth disadvantage for malignant B cells in the presence of ibrutinib (or PI3K inhibitor idelalisib) in vitro and in vivo. FoxO1/Rictor/pAktS473 axis represents an early non-genetic adaptation to BCR inhibitor therapy not requiring PI3Kδ or BTK kinase activity. We further demonstrate that FoxO1 can be targeted therapeutically, and its inhibition induces CLL cells' apoptosis alone or in combination with BTK inhibitors (ibrutinib, acalabrutinib, pirtobrutinib) and blocks their proliferation triggered by T-cell factors (CD40L, IL-4, and IL-21).

中文翻译：

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在慢性淋巴细胞白血病中，FoxO1/Rictor 轴通过 Akt 激活诱导对依鲁替尼的非遗传适应。


BTK 抑制剂治疗在持续数月的慢性淋巴细胞白血病 （CLL） 中诱导外周血淋巴细胞增多。目前尚不清楚是否存在非遗传适应机制，允许 CLL 细胞在 BTK 抑制剂诱导的淋巴细胞增多期间存活和/或在治疗耐药中发挥作用。我们表明，在大约 70% 的 CLL 病例中，体内依鲁替尼治疗在几周内使 Akt 活性高于治疗前水平，导致代偿性 CLL 细胞存活和治疗时更明显的淋巴细胞增多。依鲁替尼诱导的 Akt 磷酸化 （pAktS473） 是由 FoxO1 转录因子的上调引起的，该转录因子诱导 Rictor 的表达，Rictor 是一种 mTORC2 蛋白复合物的组装蛋白，可在丝氨酸 473 （S473） 位点直接磷酸化 Akt。在依鲁替尼（或 PI3K 抑制剂 idelalisib）存在下，FoxO1 或 Rictor 的敲除或抑制导致体外和体内恶性 B 细胞的 Akt 磷酸化和生长劣势显着降低。FoxO1/Rictor/pAktS473 轴代表对不需要 PI3Kδ 或 BTK 激酶活性的 BCR 抑制剂治疗的早期非遗传适应。我们进一步证明 FoxO1 可以靶向治疗，其抑制作用单独或与 BTK 抑制剂 （依鲁替尼、阿卡替尼、吡托布替尼） 联合诱导 CLL 细胞凋亡，并阻断其由 T 细胞因子 （CD40L、IL-4 和 IL-21） 触发的增殖。