Institute of Molecular Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York.
Department of Medicine, Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York.
Clin Cancer Res. 2023 May 15;29(10):1984-1995. doi: 10.1158/1078-0432.CCR-22-2386.
Inhibitors of Bruton's tyrosine kinase (BTKi) and PI3K (PI3Ki) have significantly improved therapy of chronic lymphocytic leukemia (CLL). However, the emergence of resistance to BTKi has introduced an unmet therapeutic need. Hence, we sought evidence for essential roles of PI3K-δi and PI3K-γi in treatment-naïve and BTKi-refractory CLL.
Responses to PI3K-δi, PI3K-γi, and the dual-inhibitor duvelisib in each B, T, and myeloid cell compartments of CLL were studied in vitro, and in a xenograft mouse model using primary cells from treatment-naïve and ibrutinib-resistant patients, and finally, in a patient with ibrutinib-resistant CLL treated with duvelisib.
We demonstrate the essential roles of PI3K-δ for CLL B-cell survival and migration, of PI3K-γ for T-cell migration and macrophage polarization, and of dual inhibition of PI3K-δ,γ for efficacious reduction of leukemia burden. We also show that samples from patients whose disease progressed on ibrutinib were responsive to duvelisib therapy in a xenograft model, irrespective of BTK mutations. In support of this, we report a patient with ibrutinib-resistant CLL, bearing a clone with BTK and PLCγ2 mutations, who responded immediately to single-agent duvelisib with redistribution lymphocytosis followed by a partial clinical remission associated with modulation of T and myeloid cells.
Our data define the mechanism of action whereby dual inhibition of PI3K-δ,γ affects CLL B-cell numbers and T and myeloid cell pro-leukemia functions and support the use of duvelisib as a valuable approach for therapeutic interventions, including for patients refractory to BTKi.
布鲁顿酪氨酸激酶（BTK）和 PI3K（PI3Ki）抑制剂显著改善了慢性淋巴细胞白血病（CLL）的治疗效果。然而，BTKi 耐药的出现带来了尚未满足的治疗需求。因此，我们寻求 PI3K-δi 和 PI3K-γi 在初治和 BTKi 耐药 CLL 中的关键作用的证据。
在体外研究了 PI3K-δi、PI3K-γi 和双重抑制剂 duvelisib 在 CLL 的 B、T 和髓样细胞区室中的作用，在使用初治和伊布替尼耐药患者的原代细胞的异种移植小鼠模型中进行了研究，最后在一例伊布替尼耐药 CLL 患者中进行了 duvelisib 治疗。
我们证明了 PI3K-δ 对 CLL B 细胞存活和迁移的关键作用，PI3K-γ 对 T 细胞迁移和巨噬细胞极化的关键作用，以及 PI3K-δ、γ 的双重抑制对有效减少白血病负担的作用。我们还表明，在异种移植模型中，那些疾病在伊布替尼进展的患者的样本对 duvelisib 治疗有反应，无论 BTK 突变如何。支持这一点，我们报告了一例伊布替尼耐药的 CLL 患者，该患者携带 BTK 和 PLCγ2 突变的克隆，该患者对单药 duvelisib 立即有反应，表现为淋巴细胞重新分布，随后出现部分临床缓解，同时伴有 T 细胞和髓样细胞的调节。
我们的数据定义了 PI3K-δ、γ 双重抑制影响 CLL B 细胞数量以及 T 和髓样细胞促白血病功能的作用机制，并支持将 duvelisib 用作包括对 BTKi 耐药患者在内的治疗干预的有价值方法。
