Rational polypharmacological targeting of FLT3, JAK2, ABL, and ERK1 suppresses the adaptive resistance to FLT3 inhibitors in AML.
Rational polypharmacological targeting of FLT3, JAK2, ABL, and ERK1 suppresses the adaptive resistance to FLT3 inhibitors in AML.
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DOI：
10.1182/bloodadvances.2022007486
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发表时间：
2023-04-25
期刊：
影响因子：
7.5
通讯作者：
Azam, Mohammad
中科院分区：
文献类型：
--
作者：
Azhar, Mohammad;Kincaid, Zachary;Kesarwani, Meenu;Menke, Jacob;Schwieterman, Joshua;Ansari, Sekhu;Reaves, Angela;Ahmed, Arhama;Shehzad, Rammsha;Khan, Areeba;Syed, Nuha;Amir, Noor;Wunderlich, Mark;Latif, Tahir;Seibel, William;Azam, Mohammad
JAK 2、ABL和MAPK信号传导驱动对FLT 3抑制剂的适应性抗性。FLT 3、JAK 2、ABL和MAPK信号传导的多药理学靶向在AML中提供持久的应答。尽管在开发选择性FMS样酪氨酸激酶3（FLT 3）抑制剂方面取得了重大进展，但即使在持续治疗中，对治疗的抗性也很常见。获得靶向突变或适应MAPK、JAK 2和ABL信号通路会导致治疗失败和疾病复发。尽管在临床前模型中所有逃逸途径的组合靶向证明了其有效性，但由于药物-药物相互作用和抑制剂的不同药代动力学，临床应用具有挑战性。我们推断，选择性的多药靶向可能导致持久的反应，降低毒性。进行基于细胞的筛选以鉴定靶向FLT 3、RAS-MAPK、BCR-ABL和JAK 2的抑制剂，以靶向用FLT 3抑制剂观察到的适应性抗性。在这里，我们表明，pluripotin是一个等效的抑制剂FLT 3，BCR-ABL，JAK 2除了抑制Ras-GAP和细胞外信号调节激酶1（ERK 1）。结构建模研究表明，pluripotin是一种II型激酶抑制剂，可选择性地与FLT 3、ABL和JAK 2的非活性构象结合。Pluripotin对表达FLT 3 ITD的小鼠和人细胞均显示出强效抑制活性，包括看门人残基F691 L的临床挑战性耐药突变。同样，pluripotin抑制了由RAS-MAPK通路、BCR-ABL和JAK 2信号传导的激活所赋予的适应性抗性。用pluripotin治疗抑制了多种体内模型中急性髓性白血病（AML）的进展，包括小鼠异种移植物中的患者来源的原代AML细胞。作为概念证明，我们证明了驱动适应性抗性的关键信号节点的靶向多药抑制可以提供持久的反应。
JAK2, ABL, and MAPK signaling drive adaptive resistance to FLT3 inhibitors. Polypharmacological targeting of FLT3, JAK2, ABL, and MAPK signaling provides a durable response in AML. Despite significant advancements in developing selective FMS-like tyrosine kinase 3 (FLT3) inhibitors, resistance to treatment is common even on continued therapy. Acquisition of on-target mutations or adaptation to MAPK, JAK2, and ABL signaling pathways drive treatment failure and disease relapse. Although combinatorial targeting of all escape routes in preclinical models demonstrated its efficacy, the clinical application is challenging owing to drug-drug interaction and differing pharmacokinetics of the inhibitors. We reasoned that selective polypharmacological targeting could lead to a durable response with reduced toxicity. A cell-based screening was carried out to identify inhibitors targeting FLT3, RAS-MAPK, BCR-ABL, and JAK2 to target the adaptive resistance observed with FLT3 inhibitors. Here, we show that pluripotin is an equipotent inhibitor of FLT3, BCR-ABL, and JAK2 in addition to inhibiting Ras-GAP and extracellular signal-regulated kinase 1 (ERK1). Structural modeling studies revealed that pluripotin is a type II kinase inhibitor that selectively binds with inactive conformations of FLT3, ABL, and JAK2. Pluripotin showed potent inhibitory activity on both mouse and human cells expressing FLT3ITD, including clinically challenging resistant mutations of the gatekeeper residue, F691L. Likewise, pluripotin suppressed the adaptive resistance conferred by the activation of RAS-MAPK pathways, BCR-ABL, and JAK2 signaling. Treatment with pluripotin curbed the progression of acute myeloid leukemia (AML) in multiple in vivo models including patient-derived primary AML cells in mouse xenotransplants. As a proof of concept, we demonstrate that targeted polypharmacological inhibition of key signaling nodes driving adaptive resistance can provide a durable response.
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影响因子：
64.5
作者：
Azam, M;Latek, RR;Daley, GQ
通讯作者：
Daley, GQ
影响因子：
20.3
作者：
Kottaridis, PD;Gale, RE;Linch, DC
通讯作者：
Linch, DC
DOI：
10.1073/pnas.0608156103
发表时间：
2006-11-14
影响因子：
11.1
作者：
Chen, Shuibing;Do, Jeong Tae;Ding, Sheng
通讯作者：
Ding, Sheng
影响因子：
--
作者：
Chen F;Ishikawa Y;Akashi A;Naoe T;Kiyoi H
通讯作者：
Kiyoi H
影响因子：
11.4
作者：
Rummelt, Christoph;Gorantla, Sivahari P.;von Bubnoff, Nikolas
通讯作者：
von Bubnoff, Nikolas