Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, China.
Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
Mol Oncol. 2020 Apr;14(4):882-895. doi: 10.1002/1878-0261.12645. Epub 2020 Feb 14.
The development of acquired resistance to osimertinib (Osim) (AZD9291 or TAGRISSO ), 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.
奥希替尼（Osim）（AZD9291 或 TAGRISSO）获得性耐药的发展，奥希替尼是一种经美国食品药品监督管理局批准的用于治疗表皮生长因子受体（EGFR）突变型非小细胞肺癌（NSCLC）的第三代 EGFR 抑制剂，限制了患者的长期获益。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，是否可用于克服奥希替尼耐药。HNK 与奥希替尼联合使用可协同降低几种奥希替尼耐药细胞系的存活率，增强抑制细胞集落形成和生长以及诱导细胞凋亡的作用。该联合用药还显示出对奥希替尼耐药异种移植瘤的更强生长抑制作用，包括裸鼠中存在 19del、T790M 和 C797S 三重突变的肿瘤。在机制上，联合用药诱导细胞凋亡的增强主要是由于通过促进其降解来增强 Mcl-1 的减少。一种合成的 HNK 衍生物具有相似的作用且疗效更强。我们的研究结果证明了在临床上进一步研究 HNK 及其衍生物以克服奥希替尼耐药的必要性。
