Lung adenocarcinoma (LAD) is a human malignancy successfully treated with the tyrosine kinase inhibitor (TKI) gefitinib; however, the enrichment of therapy resistant cancer stem cells (CSCs) in such patients is assumed to be a source of treatment failure. Evaluation of LAD cell populations treated with the TKI inhibitor gefitinib identified unique aspects of a subpopulation of tumor cells exhibiting stem-like properties and mitochondria-specific metabolic features along with their reliance on sirtuin 1 (SIRT1) for survival advantage. This addiction to bioenergetic metabolism in LAD treated with EGFR-targeted therapy suggests that mitochondrial targeting should be synthetically lethal using established cytotoxic therapies. Accordingly, loss of the phenotype present in resistant CSC clones either by targeting the energy metabolism with tigecycline, a mitochondrial DNA-translation inhibitor, or tenovin-6 (TV-6), a SIRT1 inhibitor, inhibited their dependency on mitochondrial oxidative phosphorylation (mtOXPHOS) and sensitized them for a more pronounced and long-lasting TKI therapeutic effect. The results specifically demonstrated that combined therapy with TV-6 and gefitinib resulted in tumor regression in xenograft mouse models, whereas administration of a single agent showed no such efficacy. Importantly, combined treatment with TV-6 also decreased the effective dose of gefitinib necessary for treatment response. Clinical analysis demonstrated that high-profile SIRT1 and mtOXPHOS proteins were associated with recurrence and poor prognosis in LAD patients. These observations support the CSC hypothesis for cancer relapse and advocate use of mitochondria-targeting inhibitors as part of combinatorial therapy in a variety of clinical settings, as well as for reducing first-line TKI dosage in LAD patients.

中文翻译：

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靶向组蛋白脱乙酰基酶SIRT1通过调节肺腺癌中的线粒体氧化磷酸化选择性地根除对EGFR TKI耐药的癌症干细胞。

肺腺癌（LAD）是一种用酪氨酸激酶抑制剂（TKI）吉非替尼（gefitinib）成功治疗的人类恶性肿瘤；但是，这种患者中具有治疗抗性的癌症干细胞（CSC）的富集被认为是治疗失败的根源。用TKI抑制剂吉非替尼治疗的LAD细胞群体的评估确定了肿瘤细胞亚群的独特方面，这些亚群表现出干样特性和线粒体特有的代谢特征，并依赖sirtuin 1（SIRT1）来获得生存优势。对以EGFR靶向治疗的LAD中生物能代谢的这种沉迷表明，使用既定的细胞毒性疗法，线粒体靶向应是合成致死性的。因此，通过使用替加环素靶向能量代谢，可以使抗性CSC克隆中存在的表型丧失，线粒体DNA翻译抑制剂，或SIRT1抑制剂tenovin-6（TV-6），抑制了它们对线粒体氧化磷酸化（mtOXPHOS）的依赖性，并使它们对TKI的治疗效果更加显着和持久。结果明确表明，TV-6和吉非替尼的联合治疗在异种移植小鼠模型中导致肿瘤消退，而单药给药则没有这种功效。重要的是，TV-6的联合治疗还降低了治疗反应所需的吉非替尼的有效剂量。临床分析表明，高水平的SIRT1和mtOXPHOS蛋白与LAD患者的复发和预后不良有关。