Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer

By A. Kapoor, W. Yao, Haoqiang Ying, Sujun Hua, Alison Liewen, Qiuyun Wang, Y. Zhong, Changli Wu, A. Sadanandam, Baoli Hu and 20 more. Cell, 2014

668 citations recorded by the source corpus.

SUMMARY Activating mutations in KRAS are among the most frequent events in diverse human carcinomas and are particularly prominent in human pancreatic ductal adenocarcinoma (PDAC). An inducible KrasG12D-driven mouse model of PDAC has established a critical role for sustained KrasG12D expression in tumor maintenance, providing a model to determine the potential for, and the underlying mechanisms of, KrasG12D–independent PDAC recurrence. Here we show that some tumors undergo spontaneous relapse and are devoid of KrasG12D expression and downstream canonical MAPK signaling and instead acquire amplification and overexpression of the transcriptional co-activator Yap1. Functional studies established the role of Yap1 and the transcriptional factor Tead2 in driving KrasG12D–independent tumor maintenance. The Yap1/Tead2 complex acts cooperatively with E2F transcription factors to activate a cell cycle and DNA replication program. Our studies, along with corroborating evidence from human PDAC models, portend a novel mechanism of escape from oncogenic Kras addiction in PDAC.

Subfields: Cell Biology

View Paper: https://www.semanticscholar.org/paper/89caf765a3ece9e28bad89113c478714b78a49fb

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In Cell Biology

1. K. Guan
2. S. Piccolo
3. Fa-Xing Yu
4. Bin Zhao
5. M. Cordenonsi
6. S. Dupont
7. Z. Meng
8. Duojia Pan

Citations in the corpus

• Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor. (2018, background): “…have observed heterogeneous dependence for sustained KRAS expression (<50% addicted) across KRASmutant cancer cell lines (Hayes et al., 2016; Kapoor et al., 2014; Lamba et al., 2014; Patricelli et al., 2016; Shao et al., 2014; Singh et al., 2009; Sunaga et al., 2011; Vartanian et al.,…”
• The Hippo Pathway: Biology and Pathophysiology. (2019, background): “It has been observed that YAP amplification rescued Kras-mutant pancreatic cancer cells when Kras was inhibited (48).”
• Drugging the ‘undruggable’ cancer targets (2017, positive): “Studies by Ronald DePinho’s group 47 showed that some tumours induced by Kras G12D undergo spontaneous relapse following Kras G12D ablation owing to amplification and overexpression of the Yes-associated protein 1 ( Yap1 ) transcriptional coactivator, which drives Kras G12D -independent tumour…”
• YAP/TAZ at the roots of cancer (2016, background): “The mechanisms of this response have only recently been explored in cancer cells highlighting a broad transcriptional program connected to cell cycle progression downstream of YAP/TAZ (Kapoor et al., 2014; Zanconato et al., 2015).”
• Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer. (2015, positive): “Amplification of the YAP gene has been associated with cancer relapse in KRAS-driven colon and pancreatic cancers (Kapoor et al., 2014; Shao et al., 2014).”
• The Hippo Signaling Pathway in Development and Disease (2019, background): “profiling and chromatin immunoprecipitation analysis confirmed that genes related to cell proliferation and cell death are enriched among all Hippo target genes in both Drosophila and mammals (Kapoor et al., 2014; Oh et al., 2013; Zanconato et al., 2015).”
• The biology of YAP/TAZ: hippo signaling and beyond. (2014, background): “Two recent papers studied the mechanism of tumor recurrence after K-Ras inhibition and intriguingly linked the rescue of cell survival of otherwise K-Ras-addicted tumor cells to YAP1 activation (100, 184).”