Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China; Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, China.
Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China.
Pharmacol Res. 2021 Aug;170:105701. doi: 10.1016/j.phrs.2021.105701. Epub 2021 Jun 1.
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 downregulated 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.
奥希替尼是一种第三代表皮生长因子受体酪氨酸激酶抑制剂（TKI），常用于治疗 EGFR 突变型非小细胞肺癌（NSCLC）。然而，在奥希替尼治疗后，会出现对突变型 EGFR（T790M）的获得性耐药。肺癌细胞中高活性氧（ROS）水平会影响血红素水平，并对奥希替尼耐药产生影响。在这里，我们发现奥希替尼耐药的 EGFR 突变型 NSCLC 细胞系中血红素水平升高，奥希替尼治疗的 EGFR 突变型 NSCLC 患者的血浆血红素水平也升高。抗疟药二氢青蒿素（DHA）具有抗癌作用且需要血红素，因此我们测试了它逆转奥希替尼耐药的潜力。DHA 下调了血红素加氧酶 1 的表达，并抑制了奥希替尼耐药的 EGFR 突变型 NSCLC 细胞（PC9-GR4-AZD1）的增殖，而添加 5-氨基乙酰丙酸、原卟啉 IX 和血红素则进一步增强了这种作用。DHA 与奥希替尼联合使用在抑制所有测试的奥希替尼耐药细胞系的增殖和集落形成方面具有协同作用。奥希替尼和 DHA 的联合治疗还增加了 ROS 水平，下调了几种在奥希替尼耐药的 EGFR 突变型 NSCLC 细胞中常过表达的 RTK 的磷酸化或蛋白水平，并在 PC9-GR4-AZD1 异种移植小鼠模型中抑制肿瘤生长而无毒性。结果表明，DHA 通过提高 ROS 水平和损害血红素代谢，能够逆转 EGFR 突变型 NSCLC 对奥希替尼的耐药性。
