ISCB iRNA COSI and RNA Society present
Altered RNA Splicing by Mutant p53 Activates Oncogenic RAS Signaling in Pancreatic Cancer
Presented by Luisa Escobar-Hoyos, Yale University
Plan to Watch!
Join us Thursday, October 15, 2020, 11:00 AM - 12:00 PM EDT for this jointly hosted webinar. ISCBacademy is complimenatry for all ISCB members. In partnership with the RNA Society, we are also offering this content complimentary to RNA Society members. Not a Member? You can still join for a nominal fee OR become a member and get this webinar and upcoming ones free!
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.