Cancers treated with targeted therapies against oncogene dependencies often develop resistance. Upon oncogene suppression, other genes are often able to sustain tumor survival. In a recent Cell publication, CTD2 researchers at the Dana Farber Cancer Institute revealed YAP1 as one such gene that confers resistance in KRAS-dependent colon, pancreatic, and lung cancer cell lines.
In a screen to test viability in KRAS-suppressed cancer cells, YAP1, a transcriptional co-activator, was the highest scoring gene among 147 other hits. The authors showed that YAP1 nuclear localization and transcriptional activation domains are necessary to rescue cell viability. YAP1 interacts with the transcription factor FOS to activate a transcription program that promotes epithelial to mesenchymal transition (EMT), which could allow cells to survive under KRAS-suppressed conditions. In mice with Kras-driven lung cancer, tumors that persist upon Kras suppression show Yap1 nuclear enrichment. These tumor tissues also are enriched for genes involved in EMT.
Further understanding mechanisms that confer treatment resistance, such as those presented here, may help inform development of novel therapeutics for oncogene-dependent tumors.