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


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