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

被引：125

作者：

Escobar-Hoyos, Luisa F. ^{[1
,2
,3
,4
,5
]}

Penson, Alex ^{[2
,6
]}

Kannan, Ram ^{[7
]}

Cho, Hana ^{[2
]}

Pan, Chun-Hao ^{[5
]}

Singh, Rohit K. ^{[8
]}

Apken, Lisa H. ^{[9
]}

Hobbs, G. Aaron ^{[10
]}

Luo, Renhe ^{[11
]}

Lecomte, Nicolas ^{[1
,2
]}

Babu, Sruthi ^{[5
]}

Pan, Fong Cheng ^{[1
,2
]}

Alonso-Curbelo, Direna ^{[1
,6
]}

Morris, John P. ^{[1
,6
]}

Askan, Gokce ^{[1
,2
,12
]}

Grbovic-Huezo, Olivera ^{[1
,2
,6
]}

Ogrodowski, Paul ^{[7
]}

Bermeo, Jonathan ^{[1
,2
]}

Saglimbeni, Joseph ^{[1
,2
]}

Cruz, Cristian D. ^{[1
,2
]}

Ho, Yu-Jui ^{[7
]}

Lawrence, Sharon A. ^{[1
,2
,13
]}

Melchor, Jerry P. ^{[1
,2
]}

Goda, Grant A. ^{[14
,15
]}

Bai, Karen ^{[5
]}

Pastore, Alessandro ^{[2
]}

Hogg, Simon J. ^{[2
]}

Raghavan, Srivatsan ^{[16
,17
]}

Bailey, Peter ^{[18
,19
]}

Chang, David K. ^{[20
,21
,22
,23
]}

Biankin, Andrew ^{[18
,19
,20
,21
,22
]}

Shroyer, Kenneth R. ^{[5
]}

Wolpin, Brian M. ^{[16
]}

Aguirre, Andrew J. ^{[16
,17
]}

Ventura, Andrea ^{[7
]}

Taylor, Barry ^{[2
,6
,24
,25
]}

Der, Channing J. ^{[10
,14
]}

Dominguez, Daniel ^{[10
,14
]}

Kummel, Daniel ^{[8
]}

Oeckinghaus, Andrea ^{[9
]}

Lowe, Scott W. ^{[1
,7
,26
]}

Bradley, Robert K. ^{[27
]}

Abdel-Wahab, Omar ^{[2
]}

Leach, Steven D. ^{[1
,2
,13
,28
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, David M Rubenstein Ctr Pancreat Canc Res, New York, NY 10065 USA

[2] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[3] Yale Univ, Sch Med, Dept Therapeut Radiol, New Haven, CT 06520 USA

[4] Univ Cauca, Sch Nat Sci & Educ, Dept Biol, Res Grp Genet Toxicol & Cytogenet, Popayan, Colombia

[5] SUNY Stony Brook, Renaissance Sch Med, Dept Pathol, New York, NY 11794 USA

[6] Mem Sloan Kettering Canc Ctr, Marie Jose & Henry R Kravis Ctr Mol Oncol, New York, NY 10065 USA

[7] Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, Sloan Kettering Inst, Canc Biol & Genet Program, New York, NY 10065 USA

[8] Univ Munster, Inst Biochem, Munster, Germany

[9] Univ Munster, Inst Mol Tumor Biol, Munster, Germany

[10] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27515 USA

[11] Mem Sloan Kettering Canc Ctr, Gerstner Sloan Kettering Grad Sch Biomed Sci, New York, NY 10065 USA

[12] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA

[13] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10065 USA

[14] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA

[15] Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA

[16] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[17] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[18] Heidelberg Univ, Dept Gen Surg, Neuenheimer Feld 110, D-69120 Heidelberg, Baden Wurttembe, Germany

[19] Univ Glasgow, Inst Canc Sci, Garscube Estate,Switchback Rd, Glasgow G61 1Q, Lanark, Scotland

[20] Garvan Inst Med Res, Kinghorn Canc Ctr, Sydney, NSW, Australia

[21] Garvan Inst Med Res, Canc Res Program, Sydney, NSW, Australia

[22] Bankstown Hosp, Dept Surg, Eldridge Rd, Sydney, NSW, Australia

[23] Univ New South Wales, Fac Med, South Western Sydney Clin Sch, Liverpool, NSW, Australia

[24] Mem Sloan Kettering Canc Ctr, Dept Epidemiol, New York, NY 10065 USA

[25] Mem Sloan Kettering Canc Ctr, Dept Biostat, New York, NY 10065 USA

[26] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

[27] Fred Hutchinson Canc Res Ctr Seattle, Seattle, WA 98109 USA

[28] Dartmouth Norris Cotton Canc Ctr, Lebanon, NH 03766 USA

来源：

CANCER CELL | 2020年 / 38卷 / 02期

关键词：

NUCLEAR RIBONUCLEOPROTEIN-K; DUCTAL ADENOCARCINOMA; KRAS; BINDING; TUMOR; EXPRESSION; RECEPTOR; SUBTYPES; PROTEIN; TRANSCRIPTION;

D O I：

10.1016/j.ccell.2020.05.010

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：198 / +

页数：22

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