Fürstenau Moritz, Eichhorst Barbara
German CLL Study Group, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Department I of Internal Medicine, University Hospital Cologne, University of Cologne, 50937 Cologne, Germany.
Cancer Center Cologne Essen (CCCE)-Partner Site Cologne, University of Cologne, 50937 Cologne, Germany.
Cancers (Basel). 2021 Mar 16;13(6):1336. doi: 10.3390/cancers13061336.
The approval of Bruton's tyrosine kinase (BTK) inhibitors such as ibrutinib and acalabrutinib and the Bcl-2 inhibitor venetoclax have revolutionized the treatment of chronic lymphocytic leukemia (CLL). While these novel agents alone or in combination induce long lasting and deep remissions in most patients with CLL, their use may be associated with the development of clinical resistance. In this review, we elucidate the genetic basis of acquired resistance to BTK and Bcl-2 inhibition and present evidence on resistance mechanisms that are not linked to single genomic alterations affecting these target proteins. Strategies to prevent resistance to novel agents are discussed in this review with a special focus on new combination therapies.
布鲁顿酪氨酸激酶（BTK）抑制剂（如伊布替尼和阿卡拉布替尼）以及Bcl-2抑制剂维奈克拉的获批，彻底改变了慢性淋巴细胞白血病（CLL）的治疗方式。虽然这些新型药物单独使用或联合使用可使大多数CLL患者实现持久且深度的缓解，但其使用可能会引发临床耐药。在本综述中，我们阐明了对BTK和Bcl-2抑制产生获得性耐药的遗传基础，并展示了与影响这些靶蛋白的单一基因组改变无关的耐药机制的证据。本综述讨论了预防对新型药物产生耐药的策略，特别关注新的联合疗法。
