Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Biometric Research Program, Division of Cancer Diagnosis and Treatment, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Blood Cancer Discov. 2021 Sep 14;2(6):630-647. doi: 10.1158/2643-3230.BCD-21-0063. eCollection 2021 Nov.
The use of Bruton tyrosine kinase (BTK) inhibitors to block B-cell receptor (BCR)-dependent NF-κB activation in lymphoid malignancies has been a major clinical advance, yet acquired therapeutic resistance is a recurring problem. We modeled the development of resistance to the BTK inhibitor ibrutinib in the activated B-cell (ABC) subtype of diffuse large B-cell lymphoma, which relies on chronic active BCR signaling for survival. The primary mode of resistance was epigenetic, driven in part by the transcription factor TCF4. The resultant phenotypic shift altered BCR signaling such that the GTPase RAC2 substituted for BTK in the activation of phospholipase Cγ2, thereby sustaining NF-κB activity. The interaction of RAC2 with phospholipase Cγ2 was also increased in chronic lymphocytic leukemia cells from patients with persistent or progressive disease on BTK inhibitor treatment. We identified clinically available drugs that can treat epigenetic ibrutinib resistance, suggesting combination therapeutic strategies.
In diffuse large B-cell lymphoma, we show that primary resistance to BTK inhibitors is due to epigenetic rather than genetic changes that circumvent the BTK blockade. We also observed this resistance mechanism in chronic lymphocytic leukemia, suggesting that epigenetic alterations may contribute more to BTK inhibitor resistance than currently thought.. .
布鲁顿酪氨酸激酶（BTK）抑制剂的使用阻断了淋巴恶性肿瘤中 B 细胞受体（BCR）依赖性 NF-κB 的激活，这是一项重大的临床进展，但获得性治疗耐药性是一个反复出现的问题。我们模拟了激活 B 细胞（ABC）亚型弥漫性大 B 细胞淋巴瘤对 BTK 抑制剂依鲁替尼的耐药性的发展，该亚型依赖于慢性活跃的 BCR 信号来生存。主要的耐药模式是表观遗传的，部分由转录因子 TCF4 驱动。由此产生的表型转变改变了 BCR 信号，使得 GTPase RAC2 取代 BTK 激活磷脂酶 Cγ2，从而维持 NF-κB 活性。在慢性淋巴细胞白血病患者中，我们还观察到在 BTK 抑制剂治疗中持续或进展性疾病患者的细胞中，RAC2 与磷脂酶 Cγ2 的相互作用也增加了。我们确定了可用于治疗表观遗传依鲁替尼耐药性的临床药物，这表明了联合治疗策略。
在弥漫性大 B 细胞淋巴瘤中，我们表明 BTK 抑制剂的原发性耐药是由于表观遗传而不是绕过 BTK 阻断的遗传变化引起的。我们在慢性淋巴细胞白血病中也观察到了这种耐药机制，表明表观遗传改变可能比目前认为的更有助于 BTK 抑制剂耐药性。
