Multi-kinase RET inhibitors, such as cabozantinib and RXDX-105, are active in lung cancer patients with RET fusions; however, the overall response rates to these two drugs are unsatisfactory compared to other targeted therapy paradigms. Moreover, these inhibitors may have different efficacies against RET rearrangements depending on the upstream fusion partner. A comprehensive preclinical analysis of the efficacy of RET inhibitors is lacking due to a paucity of disease models harboring RET rearrangements. Here we generated two new patient-derived xenograft (PDX) models, one new patient-derived cell line, one PDX-derived cell line, and several isogenic cell lines with RET fusions. Using these models, we re-examined the efficacy and mechanism of action of cabozantinib and found that this RET inhibitor was effective at blocking growth of cell lines, activating caspase 3/7 and inhibiting activation of ERK and AKT. Cabozantinib treatment of mice bearing RET-fusion-positive cell line xenografts and two PDXs significantly reduced tumor proliferation without adverse toxicity. Moreover, cabozantinib was effective at reducing growth of a lung cancer PDX that was not responsive to RXDX-105. Transcriptomic analysis of lung tumors and cell lines with RET alterations showed activation of a MYC signature and this was suppressed by treatment of cell lines with cabozantinib. MYC protein levels were rapidly depleted following cabozantinib treatment. Taken together, our results demonstrate that cabozantinib is an effective agent in preclinical models harboring RET rearrangements with three different 5' fusion partners (CCDC6, KIF5B and TRIM33). Notably, we identify MYC as a protein that is upregulated by RET expression and down-regulated by cabozantinib treatment, opening up potentially new therapeutic avenues for combinatorial targeting RET-fusion driven lung cancers. The novel RET fusion-dependent preclinical models described herein represent valuable tools for further refinement of current therapies and the evaluation of novel therapeutic strategies.

中文翻译：

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在新型患者来源的 RET 融合阳性肺腺癌模型中，RET 抑制揭示了 MYC 上调的作用。


多激酶 RET 抑制剂，如卡博替尼和 RXDX-105，对RET融合的肺癌患者有效；然而，与其他靶向治疗范例相比，这两种药物的总体反应率并不令人满意。此外，这些抑制剂可能对RET重排具有不同的功效，具体取决于上游融合伴侣。由于缺乏携带RET重排的疾病模型，因此缺乏对 RET 抑制剂功效的全面临床前分析。在这里，我们生成了两种新的患者来源的异种移植 (PDX) 模型、一种新的患者来源的细胞系、一种 PDX 来源的细胞系和几种具有 RET 融合的同基因细胞系。利用这些模型，我们重新检验了卡博替尼的功效和作用机制，发现这种 RET 抑制剂可有效阻断细胞系的生长、激活 caspase 3/7 并抑制 ERK 和 AKT 的激活。卡博替尼治疗携带 RET 融合阳性细胞系异种移植物和两个 PDX 的小鼠可显着减少肿瘤增殖，且无不良毒性。此外，卡博替尼可有效减少对 RXDX-105 无反应的肺癌 PDX 的生长。对肺肿瘤和具有 RET 改变的细胞系的转录组分析显示 MYC 特征的激活，并且用卡博替尼处理细胞系可以抑制这种激活。卡博替尼治疗后，MYC 蛋白水平迅速降低。总而言之，我们的结果表明，卡博替尼在具有三种不同 5' 融合伴侣（ CCDC6 、 KIF5B和TRIM33 ）的RET重排的临床前模型中是一种有效的药物。 值得注意的是，我们将 MYC 确定为一种通过 RET 表达上调并通过卡博替尼治疗下调的蛋白质，为组合靶向 RET 融合驱动的肺癌开辟了潜在的新治疗途径。本文描述的新型 RET 融合依赖性临床前模型代表了进一步完善当前疗法和评估新型治疗策略的宝贵工具。