Yap1 Activation Enables Bypass of Oncogenic Kras Addiction in Pancreatic Cancer

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2014 Jun 24

PMID 24954535

Citations 400

Authors

Avnish Kapoor

Wantong Yao

Haoqiang Ying

Sujun Hua

Alison Liewen

Qiuyun Wang

Yi Zhong

Chang-Jiun Wu

Anguraj Sadanandam

Baoli Hu

Qing Chang

Gerald C Chu

Ramsey Al-Khalil

Shan Jiang

Hongai Xia

Eliot Fletcher-Sananikone

Carol Lim

Gillian I Horwitz

Andrea Viale

Piergiorgio Pettazzoni

Nora Sanchez

Huamin Wang

Alexei Protopopov

Jianhua Zhang

Timothy Heffernan

Randy L Johnson

Lynda Chin

Y Alan Wang

Giulio Draetta

Ronald A DePinho

Affiliations

Soon will be listed here.

Abstract

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 Kras(G12D)-driven mouse model of PDAC has established a critical role for sustained Kras(G12D) expression in tumor maintenance, providing a model to determine the potential for and the underlying mechanisms of Kras(G12D)-independent PDAC recurrence. Here, we show that some tumors undergo spontaneous relapse and are devoid of Kras(G12D) expression and downstream canonical MAPK signaling and instead acquire amplification and overexpression of the transcriptional coactivator Yap1. Functional studies established the role of Yap1 and the transcriptional factor Tead2 in driving Kras(G12D)-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.

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