Details

Autor(en) / Beteiligte

• Escobar-Hoyos, Luisa F.
• Penson, Alex
• Kannan, Ram
• Cho, Hana
• Pan, Chun-Hao
• Singh, Rohit K.
• Apken, Lisa H.
• Hobbs, G. Aaron
• Luo, Renhe
• Lecomte, Nicolas
• Babu, Sruthi
• Pan, Fong Cheng
• Alonso-Curbelo, Direna
• Morris, John P.
• Askan, Gokce
• Grbovic-Huezo, Olivera
• Ogrodowski, Paul
• Bermeo, Jonathan
• Saglimbeni, Joseph
• Cruz, Cristian D.
• Ho, Yu-Jui
• Lawrence, Sharon A.
• Melchor, Jerry P.
• Goda, Grant A.
• Bai, Karen
• Pastore, Alessandro
• Hogg, Simon J.
• Raghavan, Srivatsan
• Bailey, Peter
• Chang, David K.
• Biankin, Andrew
• Shroyer, Kenneth R.
• Wolpin, Brian M.
• Aguirre, Andrew J.
• Ventura, Andrea
• Taylor, Barry
• Der, Channing J.
• Dominguez, Daniel
• Kümmel, Daniel
• Oeckinghaus, Andrea
• Lowe, Scott W.
• Bradley, Robert K.
• Abdel-Wahab, Omar
• Leach, Steven D.

Titel

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

Ist Teil von

• Cancer cell, 2020-08, Vol.38 (2), p.198-211.e8

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2020

Quelle

Elsevier ScienceDirect Journals

Beschreibungen/Notizen

• 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. [Display omitted] •Missense mutations in p53 are associated with specific changes in RNA splicing.•The effects of mutant p53 on RNA splicing are via the RNA binding protein hnRNPK.•Mutant p53 promotes isoforms of GAPs which enhance RAS GTP levels.•Modulating GAP splicing has therapeutic potential in p53 mutant pancreas cancer. Escobar-Hoyos et al. reveal that mutant p53 can regulate RNA splicing to increase KRAS activity in pancreatic cancer. Targeting this splicing axis in mutant p53 pancreatic cancer reduces tumor growth and KRAS signaling, indicating a putative therapeutic strategy for this hard-to-treat cancer.