Ibrutinib and venetoclax target distinct subpopulations of CLL cells: implication for residual disease eradication.
Ibrutinib and venetoclax target distinct subpopulations of CLL cells: implication for residual disease eradication.
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DOI：
10.1038/s41408-021-00429-z
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发表时间：
2021-02-18
影响因子：
12.8
通讯作者：
Wang YL
中科院分区：
文献类型：
--
作者：
Lu P;Wang S;Franzen CA;Venkataraman G;McClure R;Li L;Wu W;Niu N;Sukhanova M;Pei J;Baldwin DA;Nejati R;Wasik MA;Khan N;Tu Y;Gao J;Chen Y;Ma S;Larson RA;Wang YL
伊布替尼抑制布鲁顿酪氨酸激酶，而维奈托克是抗凋亡蛋白BCL 2的特异性抑制剂。这两种药物作为单药治疗慢性淋巴细胞白血病（CLL）都非常有效，并且使用联合治疗的临床试验在完全缓解率和不可检测的微小残留病频率方面产生了显着的结果。然而，仍然缺乏药物组合成功背后的实验室原理。更好地了解这两种药物如何协同作用，最终将有助于开发其他合理的组合策略。使用促进CLL增殖的离体模型，我们表明，建模的伊鲁替尼增殖反应，但不是活力反应，与患者的实际临床反应很好地相关。重要的是，我们首次证明了伊替尼和维奈托克作用于具有不同增殖能力的不同CLL亚群。虽然CLL的分裂亚群对伊鲁替尼有反应，但静息亚群优先对维奈托克有反应。在大多数情况下，这些靶向治疗的组合有效地减少了静息和分裂亚群。我们的实验室发现有助于解释几个临床观察，并有助于了解肿瘤动力学。此外，我们的增殖模型可用于鉴定具有根除残留疾病潜力的新型药物组合。
Ibrutinib inhibits Bruton tyrosine kinase while venetoclax is a specific inhibitor of the anti-apoptotic protein BCL2. Both drugs are highly effective as monotherapy against chronic lymphocytic leukemia (CLL), and clinical trials using the combination therapy have produced remarkable results in terms of rate of complete remission and frequency of undetectable minimal residual disease. However, the laboratory rationale behind the success of the drug combination is still lacking. A better understanding of how these two drugs synergize would eventually help develop other rational combination strategies. Using an ex vivo model that promotes CLL proliferation, we show that modeled ibrutinib proliferative responses, but not viability responses, correlate well with patients’ actual clinical responses. Importantly, we demonstrate for the first time that ibrutinib and venetoclax act on distinct CLL subpopulations that have different proliferative capacities. While the dividing subpopulation of CLL responds to ibrutinib, the resting subpopulation preferentially responds to venetoclax. The combination of these targeted therapies effectively reduced both the resting and dividing subpopulations in most cases. Our laboratory findings help explain several clinical observations and contribute to the understanding of tumor dynamics. Additionally, our proliferation model may be used to identify novel drug combinations with the potential of eradicating residual disease.
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影响因子：
5.7
作者：
Calissano, Carlo;Damle, Rajendra N.;Chiorazzi, Nicholas
通讯作者：
Chiorazzi, Nicholas
影响因子：
2.4
作者：
Herishanu, Yair;Katz, Ben-Zion;Lipsky, Andrew;Wiestner, Adrian
通讯作者：
Wiestner, Adrian
影响因子：
28.5
作者：
Kashyap MK;Amaya-Chanaga CI;Kumar D;Simmons B;Huser N;Gu Y;Hallin M;Lindquist K;Yafawi R;Choi MY;Amine AA;Rassenti LZ;Zhang C;Liu SH;Smeal T;Fantin VR;Kipps TJ;Pernasetti F;Castro JE
通讯作者：
Castro JE
DOI：
10.1158/1078-0432.ccr-14-2809
发表时间：
2015-08-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Cervantes-Gomez F;Lamothe B;Woyach JA;Wierda WG;Keating MJ;Balakrishnan K;Gandhi V
通讯作者：
Gandhi V
影响因子：
20.3
作者：
Herman, Sarah E. M.;Gordon, Amber L.;Byrd, John C.
通讯作者：
Byrd, John C.