背景:对奥希替尼的获得性耐药限制了其在EGFR突变的非小细胞肺癌(NSCLC)中的临床疗效。红豆杉的广泛认可。mairei(LeméeetLévl)ChengetL.K.Fu(中国紫杉)作为天然抗癌药物是公认的。然而,红豆杉的具体贡献。mairei(LeméeetLévl)ChengetL.K.Fu在解决奥希替尼耐药性方面仍不确定。
目的:基于生物学行为和脂质代谢,我们调查了红豆杉的水提取物是否var。mairei(LeméeetLévl)ChengetL.K.Fu(AETC)通过研究其确切机制,可以增强奥希替尼在NSCLC中的抗肿瘤作用。
方法:通过细胞活力测量评估AETC对奥希替尼敏感性的增强作用,活性氧(ROS)的水平,凋亡,和脂质水平。Western印迹用于验证AETC通过ERK1/2过表达和敲低模型克服奥希替尼抗性的机制。在裸小鼠中使用来自奥希替尼抗性细胞的皮下异种移植物进行体内验证。
结果:奥希替尼耐药细胞显示胆固醇生物合成改变,ERK1/2激活诱导。AETC和奥希替尼的组合可以协同降低细胞中的ROS水平,增强细胞凋亡,并抑制奥希替尼耐药细胞的生长。机制实验表明,AETC可以通过调节ERK1/2下调胆固醇生物合成的关键调节因子,抑制胆固醇的内源性合成速率,并抑制奥希替尼耐药细胞和异种移植肿瘤中的脂质水平,最终逆转对奥希替尼的耐药性。
结论:奥希替尼耐药受胆固醇生物合成的显著影响,强调其在这方面的关键作用。AETC可通过ERK/SREBP-2/HMGCR介导的胆固醇生物合成增强奥希替尼敏感性。这些结果为奥希替尼耐药提供了有希望的治疗靶点和潜在的治疗选择。
BACKGROUND: Acquired resistance to osimertinib limits its clinical efficacy in non-small cell lung cancer (NSCLC) with EGFR mutations. The widespread recognition of Taxus chinensis var. Mairei (Lemée et Lévl) Cheng et L.K. Fu (Chinese yew) as a natural anti-cancer medication is well-established. However, the specific contribution of Taxus chinensis var. Mairei (Lemée et Lévl) Cheng et L.K. Fu in addressing resistance to osimertinib is still uncertain.
OBJECTIVE: Based on the biological behaviors and lipid metabolism, we investigated whether aqueous extract of Taxus chinensis var. Mairei (Lemée et Lévl) Cheng et L.K. Fu (AETC) could enhance the antitumor effect of osimertinib in NSCLC with an investigation on the precise mechanisms.
METHODS: The effect of AETC on enhancing osimertinib sensitivity was assessed via cell viability measurements, levels of reactive oxygen species (ROS), apoptosis, and lipid levels. Western blotting was used to verify the mechanisms of AETC responsible for overcoming the resistance to osimertinib via ERK1/2 overexpression and knockdown models. In vivo validation was conducted using subcutaneous xenografts from osimertinib-resistant cells in nude mice.
RESULTS: Osimertinib-resistant cells exhibited altered cholesterol biosynthesis, which was induced by ERK1/2 activation. The combination of AETC and osimertinib can synergistically decrease the levels of ROS in cells, enhance apoptosis, and inhibit the growth of osimertinib-resistant cells. Mechanistic experiments demonstrated that AETC can downregulate the key regulators of cholesterol biosynthesis by regulating ERK1/2, inhibiting the endogenous synthesis rate of cholesterol, and suppressing the level of lipids in osimertinib-resistant cells and xenograft tumors when combined with osimertinib, ultimately reversing resistance to osimertinib.
CONCLUSIONS: The resistance to osimertinib is significantly influenced by cholesterol biosynthesis, highlighting its pivotal role in this context. AETC can enhance osimertinib sensitivity via ERK/SREBP-2/HMGCR-mediated cholesterol biosynthesis. These results provide a promising therapeutic target and potential treatment option for resistance to osimertinib.