Brandon S. Willis, Kevin Mongeon, Hannah Dry, India L. Neveras, Nadezda Bryan, Meghana Pandya, Justine Roderick-Richardson, Wendan Xu, Li Yang, Alan Rosen, Corinne Reimer, Liliana Tuskova, Pavel Klener, Jerome T. Mettetal, Georg Lenz, Simon T. Barry
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引用次数: 0
摘要
针对 B 细胞恶性肿瘤中的 PI3K/AKT/PTEN 信号的治疗潜力仍然很有吸引力。虽然 PI3K-α/δ 抑制剂对某些 B 细胞淋巴瘤有临床疗效,但 PI3K 信号抑制剂对复发/难治性弥漫大 B 细胞淋巴瘤(DLBCL)的疗效不佳,部分原因是治疗相关毒性。在临床上,AKT 抑制剂表现出不同的耐受性,为治疗 B 细胞恶性肿瘤患者提供了另一种方法。为了探索 AKT 抑制如何与治疗 DLBCL 患者的其他潜在疗法相辅相成,我们对一组 DLCBL 细胞系进行了体外联合筛选。AKT抑制剂capivasertib与BCL-2抑制剂venetoclax联用,在DLBCL临床前模型中产生了显著的治疗效果。Capivasertib 和 venetoclax 能迅速诱导 GCB-DLBCL PTEN 野生型细胞系和那些携带 PTEN 突变或 PTEN 蛋白减少的细胞系中的 Caspase 和 PARP 分裂,从而延长 DLBCL 细胞系和患者异种移植淋巴瘤模型中的肿瘤生长抑制。在RCHOP难治性DLBCL体内模型中,加入利妥昔单抗进一步加深了capivasertib和venetoclax反应的持久性。这些发现为分别使用capivasertib和venetoclax的AKT和BCL-2抑制剂与抗CD20抗体辅助治疗DLBCL患者提供了合理的临床前证据。
Potent combination benefit of the AKT inhibitor capivasertib and the BCL-2 inhibitor venetoclax in diffuse large B cell lymphoma
The therapeutic potential of targeting PI3K/AKT/PTEN signalling in B-cell malignancies remains attractive. Whilst PI3K-α/δ inhibitors demonstrate clinical benefit in certain B-cell lymphomas, PI3K signalling inhibitors have been inadequate in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) in part, due to treatment related toxicities. Clinically, AKT inhibitors exhibit a differentiated tolerability profile offering an alternative approach for treating patients with B-cell malignancies. To explore how AKT inhibition complements other potential therapeutics in the treatment of DLBCL patients, an in vitro combination screen was conducted across a panel of DLCBL cell lines. The AKT inhibitor, capivasertib, in combination with the BCL-2 inhibitor, venetoclax, produced notable therapeutic benefit in preclinical models of DLBCL. Capivasertib and venetoclax rapidly induced caspase and PARP cleavage in GCB-DLBCL PTEN wildtype cell lines and those harbouring PTEN mutations or reduced PTEN protein, driving prolonged tumour growth inhibition in DLBCL cell line and patient derived xenograft lymphoma models. The addition of the rituximab further deepened the durability of capivasertib and venetoclax responses in a RCHOP refractory DLBCL in vivo models. These findings provide preclinical evidence for the rational treatment combination of AKT and BCL-2 inhibitors using capivasertib and venetoclax respectively alongside anti-CD20 antibody supplementation for treatment of patients with DLBCL.
期刊介绍:
Title: Leukemia
Journal Overview:
Publishes high-quality, peer-reviewed research
Covers all aspects of research and treatment of leukemia and allied diseases
Includes studies of normal hemopoiesis due to comparative relevance
Topics of Interest:
Oncogenes
Growth factors
Stem cells
Leukemia genomics
Cell cycle
Signal transduction
Molecular targets for therapy
And more
Content Types:
Original research articles
Reviews
Letters
Correspondence
Comments elaborating on significant advances and covering topical issues