The clinical success of EGFR inhibitors in EGFR-mutant lung cancer is limited by the eventual development of acquired resistance. We hypothesize that enhancing apoptosis through combination therapies can eradicate cancer cells and reduce the emergence of drug-tolerant persisters. Through high-throughput screening of a custom library of ∼1,000 compounds, we discover Aurora B kinase inhibitors as potent enhancers of osimertinib-induced apoptosis. Mechanistically, Aurora B inhibition stabilizes BIM through reduced Ser87 phosphorylation, and transactivates PUMA through FOXO1/3. Importantly, osimertinib resistance caused by epithelial-mesenchymal transition (EMT) activates the ATR-CHK1-Aurora B signaling cascade and thereby engenders hypersensitivity to respective kinase inhibitors by activating BIM-mediated mitotic catastrophe. Combined inhibition of EGFR and Aurora B not only efficiently eliminates cancer cells but also overcomes resistance beyond EMT.

EGFR抑制剂在EGFR中的临床成功- 突变肺癌受到获得性耐药的最终发展的限制。我们假设通过联合疗法增强细胞凋亡可以根除癌细胞并减少耐药性持久性细胞的出现。通过对约 1,000 种化合物的定制库进行高通量筛选，我们发现 Aurora B 激酶抑制剂是奥希替尼诱导的细胞凋亡的有效增强剂。从机制上讲，Aurora B 抑制通过减少 Ser87 磷酸化来稳定 BIM，并通过 FOXO1/3 反式激活 PUMA。重要的是，由上皮-间质转化 (EMT) 引起的奥希替尼耐药会激活 ATR-CHK1-Aurora B 信号级联反应，从而通过激活 BIM 介导的有丝分裂灾难对各自的激酶抑制剂产生超敏反应。