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Response and Resistance to BCR-ABL1-Targeted Therapies
Cancer Cell ( IF 48.8 ) Pub Date : 2020-04-13 , DOI: 10.1016/j.ccell.2020.03.006
Theodore P Braun 1 , Christopher A Eide 1 , Brian J Druker 1
Affiliation  

Chronic myeloid leukemia (CML), caused by constitutively active BCR-ABL1 fusion tyrosine kinase, has served as a paradigm for successful application of molecularly targeted cancer therapy. The development of the tyrosine kinase inhibitor (TKI) imatinib allows patients with CML to experience near-normal life expectancy. Specific point mutations that decrease drug binding affinity can produce TKI resistance, and second- and third-generation TKIs largely mitigate this problem. Some patients develop TKI resistance without known resistance mutations, with significant heterogeneity in the underlying mechanism, but this is relatively uncommon, with the majority of patients with chronic phase CML achieving long-term disease control. In contrast, responses to TKI treatment are short lived in advanced phases of the disease or in BCR-ABL1-positive acute lymphoblastic leukemia, with relapse driven by both BCR-ABL1 kinase-dependent and -independent mechanisms. Additionally, the frontline CML treatment with second-generation TKIs produces deeper molecular responses, driving disease burden below the detection limit for a greater number of patients. For patients with deep molecular responses, up to half have been able to discontinue therapy. Current efforts are focused on identifying therapeutic strategies to drive deeper molecular responses, enabling more patients to attempt TKI discontinuation.



中文翻译:


对 BCR-ABL1 靶向治疗的反应和耐药性



慢性粒细胞白血病 (CML) 由持续活跃的 BCR-ABL1 融合酪氨酸激酶引起,已成为分子靶向癌症治疗成功应用的范例。酪氨酸激酶抑制剂 (TKI) 伊马替尼的开发使 CML 患者的预期寿命接近正常。降低药物结合亲和力的特定点突变会产生 TKI 耐药性,第二代和第三代 TKI 在很大程度上缓解了这个问题。一些患者在没有已知耐药突变的情况下产生 TKI 耐药,其潜在机制具有显着异质性,但这种情况相对罕见,大多数慢性期 CML 患者实现了长期疾病控制。相比之下,在疾病晚期或 BCR-ABL1 阳性急性淋巴细胞白血病中,TKI 治疗的反应持续时间较短,且复发是由 BCR-ABL1 激酶依赖性和非依赖性机制驱动的。此外,使用第二代 TKI 进行一线 CML 治疗可产生更深层次的分子反应,使更多患者的疾病负担低于检测限。对于具有深度分子反应的患者,多达一半能够停止治疗。目前的工作重点是确定治疗策略以推动更深层次的分子反应,使更多患者能够尝试停用 TKI。

更新日期:2020-04-20
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