Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University Knight Cancer Institute, Portland, 97239, OR, USA.
Division of Hematology and Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, 97239, OR, USA.
Nat Commun. 2019 Jan 16;10(1):244. doi: 10.1038/s41467-018-08263-x.
FLT3 mutations are prevalent in AML patients and confer poor prognosis. Crenolanib, a potent type I pan-FLT3 inhibitor, is effective against both internal tandem duplications and resistance-conferring tyrosine kinase domain mutations. While crenolanib monotherapy has demonstrated clinical benefit in heavily pretreated relapsed/refractory AML patients, responses are transient and relapse eventually occurs. Here, to investigate the mechanisms of crenolanib resistance, we perform whole exome sequencing of AML patient samples before and after crenolanib treatment. Unlike other FLT3 inhibitors, crenolanib does not induce FLT3 secondary mutations, and mutations of the FLT3 gatekeeper residue are infrequent. Instead, mutations of NRAS and IDH2 arise, mostly as FLT3-independent subclones, while TET2 and IDH1 predominantly co-occur with FLT3-mutant clones and are enriched in crenolanib poor-responders. The remaining patients exhibit post-crenolanib expansion of mutations associated with epigenetic regulators, transcription factors, and cohesion factors, suggesting diverse genetic/epigenetic mechanisms of crenolanib resistance. Drug combinations in experimental models restore crenolanib sensitivity.
FLT3 突变在 AML 患者中很常见，预示着不良预后。Crenolanib 是一种强效的 I 型 pan-FLT3 抑制剂，对内部串联重复和耐药性酪氨酸激酶结构域突变均有效。虽然 crenolanib 单药治疗在经过大量预处理的复发/难治性 AML 患者中显示出临床获益，但反应是短暂的，最终会复发。在这里，为了研究 crenolanib 耐药的机制，我们对 crenolanib 治疗前后的 AML 患者样本进行了全外显子组测序。与其他 FLT3 抑制剂不同，crenolanib 不会诱导 FLT3 继发突变，FLT3 看门突变也很少见。相反，NRAS 和 IDH2 突变出现，主要是作为 FLT3 非依赖性亚克隆，而 TET2 和 IDH1 主要与 FLT3 突变克隆共存，并在 crenolanib 低反应者中富集。其余患者在 crenolanib 后表现出与表观遗传调节剂、转录因子和凝聚因子相关的突变扩展，提示 crenolanib 耐药存在多种遗传/表观遗传机制。实验模型中的药物组合恢复了 crenolanib 的敏感性。
