Division of Hematology/Oncology, University of California, San Francisco, CA, USA.
Blood. 2013 Apr 18;121(16):3165-71. doi: 10.1182/blood-2012-07-442871. Epub 2013 Feb 21.
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-naïve and select TKI-resistant FLT3-ITD+ AML patients is warranted. Alternative strategies will be required for patients with TKI-resistant FLT3-ITD D835 mutations.
FLT3 酪氨酸激酶结构域（KD）中的继发点突变是获得性临床耐药的常见原因对 FLT3 抑制剂 AC220（quizartinib）和索拉非尼。ponatinib（AP24534）是一种多激酶抑制剂，具有体外和临床活性酪氨酸激酶抑制剂（TKI）耐药性慢性髓性白血病，与 BCR-ABL KD 突变无关。ponatinib在化疗耐药性急性髓系白血病（AML）患者中具有早期临床疗效具有 FLT3 内串联重复（ITD）突变。我们评估了 ponatinib 对临床相关 FLT3-ITD 突变亚型的体外活性，这些突变亚型对 AC220 或 sorafenib 具有耐药性。FLT3“守门员”苯丙氨酸突变为亮氨酸（F691L）可轻度耐药 ponatinib，但 FLT3 激活环（AL）残基 D835 的取代可导致高度耐药。FLT3-ITD 的饱和诱变仅鉴定了 FLT3 AL 突变位置 D835、D839 和 Y842。开关控制抑制剂 DCC-2036 对 FLT3 AL 突变也没有活性。根据其对 FLT3 TKI 耐药 F691 取代的体外活性，ponatinib 在 TKI 初治和选择 TKI 耐药性 FLT3-ITD+AML 患者中的进一步临床评估是合理的。对于具有 TKI 耐药性 FLT3-ITD D835 突变的患者，需要采用替代策略。
