Abstract
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. In this study, 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. Coessentiality 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 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. Significance: This work identifies PKN2 as a core member of the Hippo signaling pathway, and its inhibition blocks YAP/TAZ-driven tumorigenesis. Furthermore, this study discovers PKN2-TAZ as arguably the most selective dependency of mesenchymal-like cancers and supports specific inhibition of PKN2 as a provocative strategy to overcome drug resistance in diverse cancer contexts. See related commentary by Shen and Tan, p. 458.