Publications

Publications Search

Search for publications by author
Search for publications by abstract keyword(s)

Altered RNA Splicing by Mutant p53 Activates Oncogenic RAS Signaling in Pancreatic Cancer

Abstract

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.

Type Journal
ISBN 1878-3686 (Electronic) 1535-6108 (Linking)
Authors Escobar-Hoyos, L. F.; Penson, A.; Kannan, R.; Cho, H.; Pan, C. H.; Singh, R. K.; Apken, L. H.; Hobbs, G. A.; Luo, R.; Lecomte, N.; Babu, S.; Pan, F. C.; Alonso-Curbelo, D.; Morris, J. P. th; Askan, G.; Grbovic-Huezo, O.; Ogrodowski, P.; Bermeo, J.; Saglimbeni, J.; Cruz, C. D.; Ho, Y. J.; Lawrence, S. A.; Melchor, J. P.; Goda, G. A.; Bai, K.; Pastore, A.; Hogg, S. J.; Raghavan, S.; Bailey, P.; Chang, D. K.; Biankin, A.; Shroyer, K. R.; Wolpin, B. M.; Aguirre, A. J.; Ventura, A.; Taylor, B.; Der, C. J.; Dominguez, D.; Kummel, D.; Oeckinghaus, A.; Lowe, S. W.; Bradley, R. K.; Abdel-Wahab, O.; Leach, S. D.
Publisher Name CANCER CELL
Published Date 2020-08-31
Published Volume 38
Published Issue 2
Published Pages 198-211 e8
Status Published in-print
DOI 10.1016/j.ccell.2020.05.010
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/32559497