Acquired resistance to tyrosine kinase inhibitors (TKIs) of epidermal growth factor receptor (EGFR) remains a clinical challenge. Especially challenging are cases in which resistance emerges through EGFR-independent mechanisms, such as through pathways that promote epithelial-to-mesenchymal transition (EMT). Through an integrated transcriptomic, proteomic, and drug screening approach, we identified activation of the yes-associated protein (YAP) and forkhead box protein M1 (FOXM1) axis as a driver of EMT-associated EGFR TKI resistance. EGFR inhibitor resistance was associated with broad multidrug resistance that extended across multiple chemotherapeutic and targeted agents, consistent with the difficulty of effectively treating resistant disease. EGFR TKI–resistant cells displayed increased abundance of spindle assembly checkpoint (SAC) proteins, including polo-like kinase 1 (PLK1), Aurora kinases, survivin, and kinesin spindle protein (KSP). Moreover, EGFR TKI–resistant cells exhibited vulnerability to SAC inhibitors. Increased activation of the YAP/FOXM1 axis mediated an increase in the abundance of SAC components in resistant cells. The clinical relevance of these finding was indicated by evaluation of specimens from patients with EGFR mutant lung cancer, which showed that high FOXM1 expression correlated with expression of genes encoding SAC proteins and was associated with a worse clinical outcome. These data revealed the YAP/FOXM1 axis as a central regulator of EMT-associated EGFR TKI resistance and that this pathway, along with SAC components, are therapeutic vulnerabilities for targeting this multidrug-resistant phenotype.

对表皮生长因子受体（EGFR）的酪氨酸激酶抑制剂（TKI）的获得性耐药仍然是临床挑战。尤其具有挑战性的情况是，通过不依赖EGFR的机制（例如通过促进上皮到间质转化（EMT）的途径）出现耐药性的情况。通过整合的转录组学，蛋白质组学和药物筛选方法，我们确定了yes相关蛋白（YAP）和叉头盒蛋白M1（FOXM1）轴的激活是EMT相关EGFR TKI抗性的驱动力。EGFR抑制剂耐药性与广泛的多药耐药性相关，后者跨越多种化学治疗和靶向药物，与有效治疗耐药性疾病的难度一致。EGFR TKI耐药细胞显示出纺锤体装配检查点（SAC）蛋白增加，包括polo样激酶1（PLK1），Aurora激酶，survivin和驱动蛋白纺锤体蛋白（KSP）。此外，EGFR TKI耐药细胞表现出对SAC抑制剂的脆弱性。YAP / FOXM1轴激活的增加介导了抗性细胞中SAC组分的丰度增加。通过评估EGFR突变型肺癌患者的标本表明了这些发现的临床相关性，表明高FOXM1表达与编码SAC蛋白的基因表达相关，并且与较差的临床结果相关。这些数据显示，YAP / FOXM1轴是EMT相关的EGFR TKI耐药性的中央调节剂，并且该途径以及SAC成分是针对这种多药耐药表型的治疗脆弱性。