Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
Clin Cancer Res. 2023 Jun 1;29(11):2144-2157. doi: 10.1158/1078-0432.CCR-22-0533.
To create an in vivo model of PDGFRA D842V-mutant gastrointestinal stromal tumor (GIST) and identify the mechanism of tumor persistence following avapritinib therapy.
We created a patient-derived xenograft (PDX) of PDGFRA D842V-mutant GIST and tested the effects of imatinib, avapritinib, and ML-7, an inhibitor of myosin light-chain kinase (MYLK). Bulk tumor RNA sequencing and oncogenic signaling were evaluated. Apoptosis, survival, and actin cytoskeleton were evaluated in GIST T1 cells and isolated PDX cells in vitro. Human GIST specimens were analyzed for MYLK expression.
The PDX was minimally responsive to imatinib but sensitive to avapritinib. Avapritinib therapy increased tumor expression of genes related to the actin cytoskeleton, including MYLK. ML-7 induced apoptosis and disrupted actin filaments in short-term cultures of PDX cells and decreased survival in GIST T1 cells in combination with imatinib or avapritinib. Combined therapy with ML-7 improved the antitumor effects of low-dose avapritinib in vivo. Furthermore, MYLK was expressed in human GIST specimens.
MYLK upregulation is a novel mechanism of tumor persistence after tyrosine kinase inhibition. Concomitant MYLK inhibition may enable the use of a lower dose of avapritinib, which is associated with dose-dependent cognitive side effects.
建立 PDGFRA D842V 突变型胃肠道间质瘤（GIST）的体内模型，并确定阿伐普利尼治疗后肿瘤持续存在的机制。
我们创建了 PDGFRA D842V 突变型 GIST 的患者来源异种移植物（PDX），并测试了伊马替尼、阿伐普利尼和肌球蛋白轻链激酶（MYLK）抑制剂 ML-7 的作用。对大量肿瘤 RNA 测序和致癌信号进行了评估。在体外评估了 GIST T1 细胞和分离的 PDX 细胞中的细胞凋亡、存活和肌动蛋白细胞骨架。分析了人类 GIST 标本中 MYLK 的表达。
PDX 对伊马替尼的反应性最低，但对阿伐普利尼敏感。阿伐普利尼治疗增加了与肌动蛋白细胞骨架相关的基因在肿瘤中的表达，包括 MYLK。ML-7 在 PDX 细胞的短期培养中诱导细胞凋亡并破坏肌动蛋白丝，并与伊马替尼或阿伐普利尼联合降低 GIST T1 细胞的存活率。联合 ML-7 治疗可改善体内低剂量阿伐普利尼的抗肿瘤作用。此外，MYLK 在人类 GIST 标本中表达。
MYLK 的上调是酪氨酸激酶抑制后肿瘤持续存在的新机制。同时抑制 MYLK 可能使低剂量阿伐普利尼的使用成为可能，而低剂量阿伐普利尼与剂量依赖性认知副作用有关。
