Shen Yandong, Crassini Kyle, Fatima Narjis, O'Dwyer Michael, O'Neill Michael, Christopherson Richard I, Mulligan Stephen P, Best O Giles
Northern Blood Research Centre, Kolling Institute, Royal North Shore Hospital, St Leonards, NSW, Australia.
School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, Australia.
Blood Adv. 2020 Oct 27;4(20):5093-5106. doi: 10.1182/bloodadvances.2019001369.
The B-cell receptor signaling pathway and dysregulation of the Bcl-2 family of proteins play crucial roles in the pathogenesis of chronic lymphocytic leukemia (CLL). Despite significant advances in the treatment of the disease, relapse and drug resistance are not uncommon. In the current study, we investigated the dual PI3/PIM kinase inhibitor IBL-202 in combination with venetoclax as a treatment option for CLL using both primary CLL cells and TP53-deficient OSU-CLL cells generated using the CRISPR-Cas9 system. IBL-202 and venetoclax were highly synergistic against primary CLL cells cocultured with CD40L fibroblasts (combination index [CI], 0.4, at a fractional effect of 0.9) and TP53-knockout (KO) OSU-CLL cells (CI, 0.5, at a fractional effect of 0.9). Synergy between the drugs was consistent, with a significant (P < .05) reduction in the 50% inhibitory concentration for both drugs. IBL-202 and venetoclax in combination induced cell-cycle arrest and slowed the proliferation of both wild-type and TP53-KO cell lines. The drug combination inhibited AKT phosphorylation, reduced expression of Bcl-xL and NF-κB, and increased the Noxa/Mcl-1 ratio. Downregulation of CXCR4 was consistent with inhibition of the SDF-1α-induced migratory capacity of CLL cells. Synergy between IBL-202 and venetoclax against primary CLL cells cultured under conditions that mimic the tumor microenvironment suggests this drug combination may be effective against CLL cells within the lymph nodes and bone marrow. Furthermore, the efficacy of the combination against the TP53-KO OSU-CLL cell line suggests the combination may be a highly effective treatment strategy for high-risk CLL.
B细胞受体信号通路以及Bcl-2家族蛋白的失调在慢性淋巴细胞白血病（CLL）的发病机制中起着关键作用。尽管该疾病的治疗取得了显著进展，但复发和耐药现象并不罕见。在本研究中，我们使用原发性CLL细胞和利用CRISPR-Cas9系统生成的TP53缺陷型OSU-CLL细胞，研究了双重PI3/PIM激酶抑制剂IBL-202与维奈托克联合使用作为CLL治疗方案的效果。IBL-202和维奈托克对与CD40L成纤维细胞共培养的原发性CLL细胞（联合指数[CI]为0.4，部分效应为0.9）以及TP53基因敲除（KO）的OSU-CLL细胞（CI为0.5，部分效应为0.9）具有高度协同作用。两种药物之间的协同作用是一致的，两种药物的50%抑制浓度均显著降低（P < 0.05）。IBL-202和维奈托克联合使用可诱导细胞周期停滞，并减缓野生型和TP53-KO细胞系的增殖。药物组合抑制了AKT磷酸化，降低了Bcl-xL和NF-κB的表达，并增加了Noxa/Mcl-1比值。CXCR4的下调与对SDF-1α诱导的CLL细胞迁移能力的抑制一致。IBL-202和维奈托克对在模拟肿瘤微环境条件下培养的原发性CLL细胞具有协同作用，这表明该药物组合可能对淋巴结和骨髓内的CLL细胞有效。此外，该组合对TP53-KO OSU-CLL细胞系的疗效表明，该组合可能是高危CLL的一种高效治疗策略。
