Cancer cells exploit a mesenchymal-like transcriptional state (MLS) to survive drug treatments. Although the MLS is well characterized, few therapeutic vulnerabilities targeting this program have been identified. Here, we systematically identify the dependency network of mesenchymal-like cancers through an analysis of gene essentiality scores in ~800 cancer cell lines, nominating a poorly studied kinase, PKN2, as a top therapeutic target of the MLS. Co-essentiality relationships, biochemical experiments, and genomic analyses of patient tumors revealed that PKN2 promotes mesenchymal-like cancer growth through a PKN2-SAV1-TAZ signaling mechanism. Notably, pairing genetic PKN2 inhibition with clinically relevant targeted therapies against EGFR, KRAS, and BRAF oncogenes suppresses drug resistance by depleting mesenchymal-like drug-tolerant persister cells. These findings provide evidence that PKN2 is a core regulator of the Hippo tumor suppressor pathway and highlight the potential of PKN2 inhibition as a generalizable therapeutic strategy to overcome drug resistance driven by the MLS across cancer contexts.

中文翻译：

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PKN2 是间充质样癌细胞状态的依赖性


癌细胞利用间充质样转录状态 （MLS） 在药物治疗中存活。尽管 MLS 的特征很好，但针对该计划的治疗脆弱性很少被发现。在这里，我们通过分析 ~800 个癌细胞系的基因必要性评分，系统地确定了间充质样癌的依赖网络，将一种研究不足的激酶 PKN2 提名为 MLS 的首要治疗靶点。患者肿瘤的共必要性关系、生化实验和基因组分析表明，PKN2 通过 PKN2-SAV1-TAZ 信号传导机制促进间充质样癌症生长。值得注意的是，将基因 PKN2 抑制与针对 EGFR、KRAS 和 BRAF 癌基因的临床相关靶向治疗相结合，通过消耗间充质样耐药持久性细胞来抑制耐药性。这些发现提供了证据，证明 PKN2 是 Hippo 抑癌途径的核心调节因子，并强调了 PKN2 抑制作为一种可推广的治疗策略的潜力，以克服 MLS 在癌症环境中驱动的耐药性。