There is an unmet clinical need to develop novel strategies to overcome resistance to tyrosine kinase inhibitors (TKIs) in patients with oncogene-driven lung adenocarcinoma (LUAD). The objective of this study was to determine if simvastatin could overcome TKI resistance using the in vitro and in vivo LUAD models. Human LUAD cell lines, tumor cells, and patient-derived xenografts (PDXs) from TKI-resistant LUAD were treated with simvastatin, either alone or in combination with a matched TKI. Tumor growth inhibition was measured by the MTS assay and expression of molecular targets was assessed by immunoblots. Tumors were assessed by histopathology, immunohistochemistry (IHC) stain, immunoblots and RNA sequencing. We found that simvastatin had a potent antitumor effect in tested LUAD cell lines and PDX tumors, regardless of tumor genotypes. Simvastatin and TKI combination did not have antagonistic cytotoxicity in these LUAD models. In an osimertinib-resistant LUAD PDX model, simvastatin and osimertinib combination resulted in a greater reduction in tumor volume than simvastatin alone (P <0.001). Immunoblots and IHC stain also confirmed that simvastatin inhibited TKI targets. In addition to inhibiting HMG-CoA reductase, RNA sequencing and Western blots identified the proliferation, migration, and invasion-related genes (such as PI3K/Akt/mTOR, YAP/TAZ, focal adhesion, extracellular matrix receptor), proteasome-related genes, and integrin (α3β1, αvβ3) signaling pathways as the significantly downregulated targets in these PDX tumors treated with simvastatin and a TKI. The addition of simvastatin is a safe approach to overcome acquired resistance to TKIs in several oncogene-driven LUAD models, which deserve further investigation.

中文翻译：

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辛伐他汀克服了患者来源的癌基因驱动的肺腺癌模型对酪氨酸激酶抑制剂的耐药性

开发新的策略来克服癌基因驱动的肺腺癌 (LUAD) 患者对酪氨酸激酶抑制剂 (TKI) 的耐药性，这一临床需求尚未得到满足。本研究的目的是确定辛伐他汀是否可以使用体外和体内 LUAD 模型克服 TKI 耐药性。人类 LUAD 细胞系、肿瘤细胞和来自 TKI 耐药 LUAD 的患者来源的异种移植物 (PDX) 单独使用辛伐他汀或与相匹配的 TKI 联合治疗。通过 MTS 测定测量肿瘤生长抑制，并通过免疫印迹评估分子靶标的表达。通过组织病理学、免疫组织化学 (IHC) 染色、免疫印迹和 RNA 测序来评估肿瘤。我们发现辛伐他汀在测试的 LUAD 细胞系和 PDX 肿瘤中具有有效的抗肿瘤作用，无论肿瘤基因型如何。辛伐他汀和 TKI 组合在这些 LUAD 模型中不具有拮抗细胞毒性。在奥希替尼耐药的 LUAD PDX 模型中，辛伐他汀和奥希替尼组合导致肿瘤体积比单独使用辛伐他汀更大（P <0.001）。免疫印迹和 IHC 染色也证实辛伐他汀抑制 TKI 靶点。除了抑制 HMG-CoA 还原酶外，RNA 测序和 Western blot 还鉴定了增殖、迁移和侵袭相关基因（如 PI3K/Akt/mTOR、YAP/TAZ、粘着斑、细胞外基质受体）、蛋白酶体相关基因，和整合素（α3β1，αvβ3）信号通路作为辛伐他汀和 TKI 治疗的 PDX 肿瘤中显着下调的靶标。在几种癌基因驱动的 LUAD 模型中，添加辛伐他汀是克服 TKI 获得性耐药的安全方法，值得进一步研究。