Dihydroartemisinin overcomes the resistance to osimertinib in EGFR-mutant non-small-cell lung cancer
Dihydroartemisinin overcomes the resistance to osimertinib in EGFR-mutant non-small-cell lung cancer
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DOI：
10.1016/j.phrs.2021.105701
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发表时间：
2021-06-14
影响因子：
9.3
通讯作者：
Cao, Peng
中科院分区：
文献类型：
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作者：
Cai, Xueting;Miao, Jing;Cao, Peng
奥希替尼是第三代 EGFR 酪氨酸激酶抑制剂 (TKI)，通常用于治疗 EGFR 突变的非小细胞肺癌 (NSCLC)。然而，奥希替尼治疗后可能会产生对突变型 EGFR (T790M) 的获得性耐药。肺癌细胞中的高活性氧 (ROS) 水平会影响血红素水平，并对奥希替尼耐药性产生影响。在这里，我们发现奥希替尼耐药的 EGFR 突变 NSCLC 细胞系中的血红素水平升高，并且奥希替尼治疗的 EGFR 突变 NSCLC 患者的血浆血红素水平也升高。抗疟药物二氢青蒿素 (DHA) 具有抗癌作用并需要血红素，经过测试以确定其恢复奥希替尼耐药性的潜力。 DHA 下调血红素加氧酶 1 的表达并抑制奥希替尼耐药的 EGFR 突变 NSCLC 细胞 (PC9-GR4-AZD1) 的细胞增殖，通过添加 5-氨基乙酰丙酸、原卟啉 IX 和氯高铁血红素可进一步增强细胞增殖。 DHA 与奥希替尼协同抑制所有测试的奥希替尼耐药细胞系的细胞增殖和集落形成。奥希替尼和 DHA 联合治疗还增加了 ROS 水平，下调了在奥希替尼耐药的 EGFR 突变 NSCLC 细胞中经常过表达的几种 RTK 的磷酸化或蛋白质水平，并在 PC9-GR4-AZD1 异种移植小鼠模型中抑制了肿瘤生长，且没有毒性。结果表明，DHA 能够通过提高 ROS 水平和损害血红素代谢来逆转 EGFR 突变 NSCLC 中对奥西替尼的耐药性。
Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), is commonly used to treat EGFR-mutant non-small-cell lung cancer (NSCLC). However, acquired resistance to mutant EGFR (T790M) can evolve following osimertinib treatment. High reactive oxygen species (ROS) levels in lung cancer cells can influence heme levels and have an impact on osimertinib resistance. Here, we found that heme levels were increased in osimertinib resistant EGFR-mutant NSCLC cell lines and plasma heme levels were also elevated in osimertinib-treated EGFR-mutant NSCLC patients. The antimalarial drug dihydroartemisinin (DHA), which has anticancer effects and requires heme, was tested to determine its potential to revert osimertinib resistance. DHA down-regulated the expression of heme oxygenase 1 and inhibited cell proliferation in osimertinib-resistant EGFR-mutant NSCLC cells (PC9-GR4-AZD1), which was further enhanced by addition of 5-aminolevulinic acid, protoporphyrin IX and hemin. DHA was synergistic with osimertinib in inhibiting cell proliferation and colony formation of all osimertinib-resistant cell lines tested. Combination treatment with osimertinib and DHA also increased the levels of ROS, downregulated the phosphorylation or protein levels of several RTKs that often are overexpressed in osimertinib-resistant EGFR-mutant NSCLC cells, and inhibited tumor growth without toxicity in a PC9-GR4-AZD1 xenograft mouse model. The results suggest that DHA is able to reverse the resistance to osimertinib in EGFR-mutant NSCLC by elevating ROS level and impair heme metabolism.