Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity. Nongenetic resistance through the activation of AURKA by its coactivator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in preclinical models. Treatment-induced activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a molecular path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA-driven residual disease and acquired resistance.

中文翻译：

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极光激酶 A 推动了肺癌对第三代 EGFR 抑制剂耐药性的演变。

尽管靶向治疗通常会引起患者最初的深刻反应，但这些影响是短暂的，因为残留的疾病会导致获得性耐药。肿瘤如何在药物反应性、耐受性和耐药性之间转变，尤其是在没有预先存在的亚克隆的情况下，仍不清楚。在表皮生长因子受体 (EGFR) 突变的肺腺癌细胞中，我们证明对 EGFR 抑制剂的残留疾病和获得性耐药需要极光激酶 A (AURKA) 活性。通过其共激活因子 TPX2 激活 AURKA 产生的非遗传耐药性是对慢性 EGFR 抑制的反应，在这种抑制作用下，它可以减轻药物诱导的细胞凋亡。极光激酶抑制剂抑制了这种适应性生存程序，增加了临床前模型中 EGFR 抑制剂反应的幅度和持续时间。治疗诱导的 AURKA 激活与体外、体内和大多数 EGFR 突变肺腺癌患者对 EGFR 抑制剂的耐药性相关。这些发现描绘了耐药性细胞产生耐药性的分子路径，并揭示了一种合成致死策略，通过抑制 AURKA 驱动的残留疾病和获得性耐药性来增强对 EGFR 抑制剂的反应。