The Transcriptional Coactivator YAP1 Substitutes for Oncogenic KRAS

Many human cancers, including pancreatic ductal adenocarcinoma (PDAC), harbor activating mutations in KRAS and exhibit a dependence on sustained expression of oncogenic KRAS for tumor survival. However, despite initial tumor regression following KRAS suppression, acquired resistance enables KRAS-independent tumor recurrence in some cases. To identify the mechanisms underlying this escape from oncogenic KRAS addiction, Kapoor, Yao, Ying, and colleagues analyzed spontaneous relapse tumors in a genetically engineered mouse model of PDAC driven by inducible Kras^G12D expression. Relapse tumors that did not reactivate Kras^G12D expression were characterized by amplification of the gene encoding the transcriptional coactivator YAP1, which was required for tumor growth in the absence of Kras^G12D and substituted for oncogenic KRAS to promote tumor maintenance. The ability of YAP1 to induce tumor recurrence was dependent on its interaction with the TEA domain family member 2 (TEAD2) transcription factor and activation of cell-cycle and DNA replication genes in cooperation with E2F1. Intriguingly, YAP1 expression was also elevated in KRAS-independent human PDAC cells. Consistent with these findings, Shao, Xue, and colleagues identified YAP1 in a genome-scale screen for genes that rescued the viability of KRAS-mutant human cancer cell lines following KRAS suppression and found that YAP1 was necessary for KRAS-induced transformation in vitro. YAP1 recapitulated oncogenic KRAS signaling and promoted tumor-cell survival via regulation of AP-1 transcription factors, in particular FOS, and coordinate stimulation of an epithelial–mesenchymal transition (EMT) transcriptional program by YAP1 and FOS. In addition, increased nuclear localization of YAP1, upregulation of YAP1 transcriptional activity, and enrichment of an EMT gene signature were associated with bypass of KRAS suppression and tumor relapse in a mouse model of KRAS-driven lung cancer. Taken together, these results establish YAP1 activation as a mechanism by which tumors may overcome KRAS dependence and suggest that inhibition of YAP1 may be therapeutically beneficial in RAS-driven cancers.

Kapoor A, Yao W, Ying H, Hua S, Liewen A, Wang Q, et al. Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer. Cell 2014;158:185–97.

Shao DD, Xue W, Krall EB, Bhutkar A, Piccioni F, Wang X, et al. KRAS and YAP1 converge to regulate EMT and tumor survival. Cell 2014;158:171–84.

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