Resisting the Resistance: Navigating BTK Mutations in Chronic Lymphocytic Leukemia (CLL).
Resisting the Resistance: Navigating BTK Mutations in Chronic Lymphocytic Leukemia (CLL).
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作者：
布鲁顿酪氨酸激酶 (BTK) 在 B 细胞受体 (BCR) 信号通路中发挥关键作用，并赋予慢性淋巴细胞白血病 (CLL) 恶性 B 细胞抗凋亡和增殖特性。小分子 BTK 抑制剂旨在结合 BTK 的活性位点并阻断下游信号传导。这些药物现已用于治疗数千名慢性淋巴细胞白血病（CLL）患者，慢性淋巴细胞白血病是西半球最常见的白血病形式。然而，早期 BTK 抑制剂的副作用和治疗耐药性导致了更新、更具选择性和非共价 BTK 抑制剂的开发。随着这些新一代 BTK 抑制剂的使用增加，新的 BTK 耐药突变已经被发现。本综述旨在讨论先前已知的和新的 BTK 突变、它们的耐药机制以及它们与患者治疗的关系。这里还讨论了未来需要进行的研究，以调查导致这些突变发生的根本原因以及它们如何引发耐药性。即将出现的试图绕过这些耐药突变的新疗法可能会遇到新的耐药突变，从而为 CLL 患者带来未满足的需求。讨论了解决所有形式耐药性的新疗法和组合。
Bruton’s tyrosine kinase (BTK) plays a key role in the B-cell receptor (BCR) signaling pathway and confers anti-apoptotic and proliferative properties to malignant B-cells in chronic lymphocytic leukemia (CLL). Small molecule BTK inhibitors were designed to bind BTK’s active site and block downstream signaling. These drugs have now been used in the treatment of thousands of patients with CLL, the most common form of leukemia in the western hemisphere. However, adverse effects of early generations of BTK inhibitors and resistance to treatment have led to the development of newer, more selective and non-covalent BTK inhibitors. As the use of these newer generation BTK inhibitors has increased, novel BTK resistance mutations have come to light. This review aims to discuss previously known and novel BTK mutations, their mechanisms of resistance, and their relationship with patient treatment. Also discussed here are future studies that are needed to investigate the underlying cause allowing these mutations to occur and how they incite resistance. New treatments on the horizon that attempt to maneuver around these resistance mutations can be met with new resistance mutations, creating an unmet need for patients with CLL. Novel therapies and combinations that address all forms of resistance are discussed.
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影响因子：
5.2
作者：
Frustaci, Anna Maria;Deodato, Marina;Zamprogna, Giulia;Cairoli, Roberto;Montillo, Marco;Tedeschi, Alessandra
通讯作者：
Tedeschi, Alessandra
影响因子：
4.7
作者：
Abbas HA;Wierda WG
通讯作者：
Wierda WG
影响因子：
5.2
作者：
Fürstenau M;Eichhorst B
通讯作者：
Eichhorst B
影响因子：
5.6
作者：
Brullo C;Villa C;Tasso B;Russo E;Spallarossa A
通讯作者：
Spallarossa A
影响因子：
7.5
作者：
Blombery, Piers;Thompson, Ella R.;Lew, Thomas E.;Tiong, Ing Soo;Bennett, Rory;Cheah, Chan Y.;Lewis, Katharine Louise;Handunnetti, Sasanka M.;Tang, Chloe Pek Sang;Roberts, Andrew;Seymour, John F.;Tam, Constantine S.
通讯作者：
Tam, Constantine S.