Journal
CANCER CELL
Volume 38, Issue 2, Pages 198-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2020.05.010
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Funding
- NIH [R01 CA204228-01, P30 CA023108]
- PanCAN-AACR grants
- Suzanne Cohn Simon Pancreatic Cancer Research Fund
- NCI [K99 CA22634201]
- National Pancreas Foundation
- Hirshberg Foundation
- NCI Cancer Center Support Grant [P30 CA08748]
- NIH/NHLBI [R01 HL128239]
- Henry & Marilyn Taub Foundation
- Edward P. Evans Foundation
- Leukemia and Lymphoma Society
- DFG [OE531/2-2, KU2531/2]
- IMF Munster [OE121701]
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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.
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