Bayer AG, Drug Discovery Oncology, Muellerstrasse 178, 13353 Berlin, Germany.
Advanced Molecular Pathology Laboratory, Singapore Health Services Pte Ltd, 20 College Road, 169856 Singapore, Singapore.
Cancer Cell. 2017 Jan 9;31(1):64-78. doi: 10.1016/j.ccell.2016.12.003.
Compared with follicular lymphoma, high PI3Kα expression was more prevalent in diffuse large B cell lymphoma (DLBCL), although both tumor types expressed substantial PI3Kδ. Simultaneous inhibition of PI3Kα and PI3Kδ dramatically enhanced the anti-tumor profile in ABC-DLBCL models compared with selective inhibition of PI3Kδ, PI3Kα, or BTK. The anti-tumor activity was associated with suppression of p-AKT and a mechanism of blocking nuclear factor-κB activation driven by CD79, CARD11, TNFAIP3, or MYD88. Inhibition of PI3Kα/δ resulted in tumor regression in an ibrutinib-resistant CD79B/MYD88 patient-derived ABC-DLBCL model. Furthermore, rebound activation of BTK and AKT was identified as a mechanism limiting CD79B-ABC-DLBCL to show a robust response to PI3K and BTK inhibitor monotherapies. A combination of ibrutinib with the PI3Kα/δ inhibitor copanlisib produced a sustained complete response in vivo in CD79B/MYD88 ABC-DLBCL models.
与滤泡性淋巴瘤相比，高 PI3Kα 表达更常见于弥漫性大 B 细胞淋巴瘤（DLBCL），尽管这两种肿瘤类型均大量表达 PI3Kδ。与选择性抑制 PI3Kδ、PI3Kα 或 BTK 相比，同时抑制 PI3Kα 和 PI3Kδ 可显著增强 ABC-DLBCL 模型中的抗肿瘤特性。抗肿瘤活性与抑制 p-AKT 相关，其机制是阻断由 CD79、CARD11、TNFAIP3 或 MYD88 驱动的核因子-κB 激活。PI3Kα/δ 抑制导致在伊布替尼耐药的 CD79B/MYD88 患者来源的 ABC-DLBCL 模型中肿瘤消退。此外，BTK 和 AKT 的反弹激活被确定为限制 CD79B-ABC-DLBCL 对 PI3K 和 BTK 抑制剂单药治疗产生强烈反应的机制。伊布替尼与 PI3Kα/δ 抑制剂 copanlisib 联合使用，可在 CD79B/MYD88 ABC-DLBCL 模型中产生持续的完全缓解。
