The development of acquired resistance to osimertinib (Osim) (AZD9291 or TAGRISSOTM ), an FDA-approved third-generation epidermal growth factor receptor (EGFR) inhibitor for the treatment of EGFR-mutant nonsmall cell lung cancer (NSCLC), limits the long-term benefits for patients. Thus, effective treatment options are urgently needed. To this end, we explored whether honokiol (HNK), a natural product with potential antitumor activity, may be used to overcome Osim resistance. The combination of HNK and Osim synergistically decreased the survival of several Osim -resistant cell lines with enhanced effects on inhibiting cell colony formation and growth and on inducing apoptosis. This combination also showed greater growth suppression of Osim-resistant xenograft tumors including those with 19del, T790M, and C797S triple mutations in nude mice. Mechanistically, the augmented induction of apoptosis by the combination is largely due to enhanced Mcl-1 reduction through facilitating its degradation. A synthetic HNK derivative exerted similar effects with greater efficacy. Our findings warrant further study of HNK and its derivatives in overcoming Osim resistance in the clinic.

中文翻译：

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用天然产物厚朴酚克服EGFR突变的NSCLC细胞对第三代EGFR抑制剂osimertinib的获得性抗性。

获得性抗药性奥西替尼（Osim）（AZD9291或TAGRISSOTM）是FDA批准的用于治疗EGFR突变型非小细胞肺癌（NSCLC）的第三代表皮生长因子受体（EGFR）抑制剂，为患者带来长期利益。因此，迫切需要有效的治疗选择。为此，我们探讨了厚朴酚（HNK）（一种具有潜在抗肿瘤活性的天然产物）是否可用于克服Osim耐药性。HNK和Osim的组合协同降低了几种Osim耐药细胞系的存活，增强了抑制细胞集落形成和生长以及诱导细胞凋亡的作用。这种组合还显示出对Osim耐药异种移植瘤（包括具有19del，T790M和C797S三重突变的裸鼠）具有更大的生长抑制作用。从机理上讲，该组合对细胞凋亡的增强诱导很大程度上归因于通过促进其降解而增强的Mcl-1还原。合成的HNK衍生物具有相似的作用，但功效更高。我们的发现值得在临床上进一步研究HNK及其衍生物克服Osim耐药性。