Activity of ponatinib against clinically-relevant AC220-resistant kinase domain mutants of FLT3-ITD
Activity of ponatinib against clinically-relevant AC220-resistant kinase domain mutants of FLT3-ITD
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DOI：
10.1182/blood-2012-07-442871
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发表时间：
2013-04-18
期刊：
影响因子：
20.3
通讯作者：
Shah, Neil P.
中科院分区：
文献类型：
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作者：
Smith, Catherine C.;Lasater, Elisabeth A.;Shah, Neil P.
Fms 样酪氨酸激酶 3 (FLT3) 酪氨酸激酶结构域 (KD) 的继发点突变是 FLT3 抑制剂 AC220（quizartinib）和索拉非尼获得性临床耐药的常见原因。 Ponatinib (AP24534) 是一种多激酶抑制剂，对于酪氨酸激酶抑制剂 (TKI) 耐药的慢性粒细胞白血病具有体外和临床活性，无论 BCR-ABL KD 突变如何。 Ponatinib 已在 FLT3 内部串联重复 (ITD) 突变的化疗耐药急性髓性白血病 (AML) 患者中证明了早期临床疗效。我们评估了 ponatinib 针对临床相关 FLT3-ITD 突变亚型（赋予 AC220 或索拉非尼耐药性）的体外活性。用亮氨酸 (F691L) 取代 FLT3“看门人”苯丙氨酸可赋予 ponatinib 轻度耐药性，但 FLT3 激活环 (AL) 残基 D835 的取代可赋予高度耐药性。 FLT3-ITD 的饱和诱变专门鉴定了位置 D835、D839 和 Y842 处的 FLT3 AL 突变。开关控制抑制剂 DCC-2036 同样对 FLT3 AL 突变没有活性。基于其针对 FLT3 TKI 耐药性 F691 替代的体外活性，有必要对 ponatinib 在未接受过 TKI 治疗和选择 TKI 耐药性 FLT3-ITD+ AML 患者中进行进一步的临床评估。对于 TKI 耐药的 FLT3-ITD D835 突变患者，需要替代策略。
Secondary point mutations in the Fms-like tyrosine kinase 3 (FLT3) tyrosine kinase domain (KD) are common causes of acquired clinical resistance to the FLT3 inhibitors AC220 (quizartinib) and sorafenib. Ponatinib (AP24534) is a multikinase inhibitor with in vitro and clinical activity in tyrosine kinase inhibitor (TKI)-resistant chronic myeloid leukemia, irrespective of BCR-ABL KD mutation. Ponatinib has demonstrated early clinical efficacy in chemotherapy-resistant acute myeloid leukemia (AML) patients with internal tandem duplication (ITD) mutations in FLT3. We assessed the in vitro activity of ponatinib against clinically relevant FLT3-ITD mutant isoforms that confer resistance to AC220 or sorafenib. Substitution of the FLT3 "gatekeeper" phenylalanine with leucine (F691L) conferred mild resistance to ponatinib, but substitutions at the FLT3 activation loop (AL) residue D835 conferred a high degree of resistance. Saturation mutagenesis of FLT3-ITD exclusively identified FLT3 AL mutations at positions D835, D839, and Y842. The switch control inhibitor DCC-2036 was similarly inactive against FLT3 AL mutations. On the basis of its in vitro activity against FLT3 TKI-resistant F691 substitutions, further clinical evaluation of ponatinib in TKI-naive and select TKI-resistant FLT3-ITD+ AML patients is warranted. Alternative strategies will be required for patients with TKI-resistant FLT3-ITD D835 mutations.