作者
Luisa F. Escobar‐Hoyos,Alex Penson,Ram Kannan,Hanna Cho,Chun‐Hao Pan,Rohit Singh,Lisa Helene Apken,G. Aaron Hobbs,Renhe Luo,Nicolas Lecomte,Sruthi Babu,Fong Cheng Pan,Direna Alonso-Curbelo,John P. Morris,Gökçe Aşkan,Olivera Grbovic-Huezo,Paul Ogrodowski,Jonathan Bermeo,Joseph A. Saglimbeni,Cristian D. Cruz,Yu-Jui Ho,Scott Lawrence,Jerry P. Melchor,Grant A. Goda,Karen Bai,Alessandro Pastore,Simon J. Hogg,Srivatsan Raghavan,Peter J. Bailey,David K. Chang,Andrew V. Biankin,Kenneth R. Shroyer,Brian M. Wolpin,Andrew J. Aguirre,Andrea Ventura,Barry S. Taylor,Channing J. Der,Daniel Domínguez,Daniel Kümmel,Andrea Oeckinghaus,Scott W. Lowe,Robert K. Bradley,Omar Abdel‐Wahab,Steven D. Leach
摘要
Pancreatic ductal adenocarcinoma (PDAC) is driven by co-existing mutations in KRAS and TP53. However, how these mutations collaborate to promote this cancer is unknown. Here, we uncover sequence-specific changes in RNA splicing enforced by mutant p53 which enhance KRAS activity. Mutant p53 increases expression of splicing regulator hnRNPK to promote inclusion of cytosine-rich exons within GTPase-activating proteins (GAPs), negative regulators of RAS family members. Mutant p53-enforced GAP isoforms lose cell membrane association, leading to heightened KRAS activity. Preventing cytosine-rich exon inclusion in mutant KRAS/p53 PDACs decreases tumor growth. Moreover, mutant p53 PDACs are sensitized to inhibition of splicing via spliceosome inhibitors. These data provide insight into co-enrichment of KRAS and p53 mutations and therapeutics targeting this mechanism in PDAC.