Are BTK and PLCG2 mutations necessary and sufficient for ibrutinib resistance in chronic lymphocytic leukemia?
Are BTK and PLCG2 mutations necessary and sufficient for ibrutinib resistance in chronic lymphocytic leukemia?
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DOI：
10.1080/17474086.2018.1435268
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发表时间：
2018-03
影响因子：
2.8
通讯作者：
Brown JR
中科院分区：
文献类型：
--
作者：
Lampson BL;Brown JR
Ibrutinib是首个对慢性淋巴细胞白血病（CLL）有效的BTK抑制剂，也是首个对患者产生耐药性的BTK抑制剂。在约80%获得性伊鲁替尼耐药的CLL患者中发现BTK和PLCG2突变，但尚不清楚这些突变是否仅与疾病复发相关或直接导致疾病复发。本文综述了CLL和伊鲁替尼的独特特性，使BTK/PLCG2突变是伊鲁替尼耐药疾病的乘客还是驱动因素的明确结论复杂化。总结了驱动耐药的突变特征，并讨论了BTK/PLCG2突变是否具有这些特征。这些特征包括：(1)在多例获得性耐药患者中进行鉴定，(2)在体外验证耐药特性，(3)相互排他性，(4)随着服药时间的增加频率增加，(5)临床复发的时间和部位频率高。虽然BTK/PLCG2突变的特征表明它们可以驱动伊鲁替尼耐药，但这一结论仍未得到正式证实，直到这种突变的特异性抑制被证明可以导致伊鲁替尼耐药CLL的消退。数据表明，在一些患者中确实存在其他的耐药机制。
Ibrutinib is the first BTK inhibitor to show efficacy in chronic lymphocytic leukemia (CLL) and is also the first BTK inhibitor to which patients have developed resistance. Mutations in BTK and PLCG2 are found in ≈80% of CLL patients with acquired resistance to ibrutinib, but it remains unclear if these mutations are merely associated with disease relapse or directly cause it. Unique properties of both CLL and ibrutinib that complicate attempts to definitively conclude whether BTK/PLCG2 mutations are passengers or drivers of ibrutinib-resistant disease are reviewed. Characteristics of mutations that drive drug resistance are summarized and whether BTK/PLCG2 mutations possess these is discussed. These characteristics include (1) identification in multiple patients with acquired resistance, (2) in vitro validation of drug-resistant properties, (3) mutual exclusivity with one another, (4) increasing frequency over time on drug, and (5) high frequency at the time and site of clinical relapse. While BTK/PLCG2 mutations have characteristics suggesting that they can drive ibrutinib resistance, this conclusion remains formally unproven until specific inhibition of such mutations is shown to cause regression of ibrutinib-resistant CLL. Data suggest that alternative mechanisms of resistance do exist in some patients.
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影响因子：
158.5
作者：
Jaenne, Pasi A.;Yang, James Chih-Hsin;Ranson, Malcolm
通讯作者：
Ranson, Malcolm
影响因子：
20.3
作者：
Bartlett, Nancy L.;Costello, Brian A.;Fehniger, Todd A.
通讯作者：
Fehniger, Todd A.
影响因子：
8.6
作者：
Graziani, Simona;Di Matteo, Gigliola;Moschese, Viviana
通讯作者：
Moschese, Viviana
慢性淋巴细胞白血病患者对 BTK 抑制产生耐药性的克隆进化
影响因子：
16.6
作者：
Burger JA;Landau DA;Taylor-Weiner A;Bozic I;Zhang H;Sarosiek K;Wang L;Stewart C;Fan J;Hoellenriegel J;Sivina M;Dubuc AM;Fraser C;Han Y;Li S;Livak KJ;Zou L;Wan Y;Konoplev S;Sougnez C;Brown JR;Abruzzo LV;Carter SL;Keating MJ;Davids MS;Wierda WG;Cibulskis K;Zenz T;Werner L;Dal Cin P;Kharchencko P;Neuberg D;Kantarjian H;Lander E;Gabriel S;O'Brien S;Letai A;Weitz DA;Nowak MA;Getz G;Wu CJ
通讯作者：
Wu CJ
DOI：
10.1158/1078-0432.ccr-14-2789
发表时间：
2015-09-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Ercan D;Choi HG;Yun CH;Capelletti M;Xie T;Eck MJ;Gray NS;Jänne PA
通讯作者：
Jänne PA