KRASG12D- and BRAFV600E-Induced Transformation of Murine Pancreatic Epithelial Cells Requires MEK/ERK-Stimulated IGF1R Signaling

被引:26
作者
Appleman, Victoria A. [1 ]
Ahronian, Leanne G. [1 ]
Cai, JiuFeng [1 ]
Klimstra, David S. [5 ]
Lewis, Brian C. [1 ,2 ,3 ,4 ]
机构
[1] Univ Massachusetts, Sch Med, Program Gene Funct & Express, Worcester, MA 01605 USA
[2] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA 01605 USA
[3] Univ Massachusetts, Sch Med, Dept Canc Biol, Worcester, MA 01605 USA
[4] Univ Massachusetts, Sch Med, Ctr Canc, Worcester, MA 01605 USA
[5] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA
关键词
GROWTH-FACTOR-I; ABL TYROSINE KINASE; K-RAS ONCOGENE; FACTOR RECEPTOR; ACTIVATED BRAF; SONIC HEDGEHOG; GENE-MUTATIONS; LUNG-CANCER; MOUSE MODEL; INHIBITION;
D O I
10.1158/1541-7786.MCR-12-0340-T
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Mutation of KRAS is a common initiating event in pancreatic ductal adenocarcinoma (PDAC). Yet, the specific roles of KRAS-stimulated signaling pathways in the transformation of pancreatic ductal epithelial cells (PDEC), putative cells of origin for PDAC, remain unclear. Here, we show that KRAS(G12D) and BRAF(V600E) enhance PDEC proliferation and increase survival after exposure to apoptotic stimuli in a manner dependent on MEK/ERK and PI3K/AKT signaling. Interestingly, we find that activation of PI3K/AKT signaling occurs downstream of MAP-ERK kinase (MEK), and is dependent on the autocrine activation of the insulin-like growth factor (IGF) receptor (IGF1R) by IGF2. Importantly, IGF1R inhibition impairs KRAS(G12D)-and BRAF(V600E)-induced survival, whereas ectopic IGF2 expression rescues KRAS(G12D)-and BRAF(V600E)-mediated survival downstream of MEK inhibition. Moreover, we show that KRAS(G12D)-and BRAF(V600E)-induced tumor formation in an orthotopic model requires IGF1R. Interestingly, we show that while individual inhibition of MEK or IGF1R does not sensitize PDAC cells to apoptosis, their concomitant inhibition reduces survival. Our findings identify a novel mechanism of PI3K/AKT activation downstream of activated KRAS, illustrate the importance of MEK/ERK, PI3K/AKT, and IGF1R signaling in pancreatic tumor initiation, and suggest potential therapeutic strategies for this malignancy. Mol Cancer Res; 10(9); 1228-39. (C) 2012 AACR.
引用
收藏
页码:1228 / 1239
页数:12
相关论文
共 48 条
  • [1] Oncogenic K-ras drives cell cycle progression and phenotypic conversion of primary pancreatic duct epithelial cells
    Agbunag, C
    Bar-Sagi, D
    [J]. CANCER RESEARCH, 2004, 64 (16) : 5659 - 5663
  • [2] Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma
    Aguirre, AJ
    Bardeesy, N
    Sinha, M
    Lopez, L
    Tuveson, DA
    Horner, J
    Redston, MS
    DePinho, RA
    [J]. GENES & DEVELOPMENT, 2003, 17 (24) : 3112 - 3126
  • [3] MOST HUMAN CARCINOMAS OF THE EXOCRINE PANCREAS CONTAIN MUTANT C-K-RAS GENES
    ALMOGUERA, C
    SHIBATA, D
    FORRESTER, K
    MARTIN, J
    ARNHEIM, N
    PERUCHO, M
    [J]. CELL, 1988, 53 (04) : 549 - 554
  • [4] Pancreatic cancer biology and genetics
    Bardeesy, N
    DePinho, RA
    [J]. NATURE REVIEWS CANCER, 2002, 2 (12) : 897 - 909
  • [5] BERGMANN U, 1995, CANCER RES, V55, P2007
  • [6] Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial
    Burris, HA
    Moore, MJ
    Andersen, J
    Green, MR
    Rothenberg, ML
    Madiano, MR
    Cripps, MC
    Portenoy, RK
    Storniolo, AM
    Tarassoff, P
    Nelson, R
    Dorr, FA
    Stephens, CD
    VanHoff, DD
    [J]. JOURNAL OF CLINICAL ONCOLOGY, 1997, 15 (06) : 2403 - 2413
  • [7] BRAF and FBXW7 (CDC4, FBW7, AGO, SEL10) mutations in distinct subsets of pancreatic cancer - Potential therapeutic targets
    Calhoun, ES
    Jones, JB
    Ashfaq, R
    Adsay, V
    Baker, SJ
    Valentine, V
    Hempen, PM
    Hilgers, W
    Yeo, CJ
    Hruban, RH
    Kern, SE
    [J]. AMERICAN JOURNAL OF PATHOLOGY, 2003, 163 (04) : 1255 - 1260
  • [8] A Central Role for RAF→MEK→ERK Signaling in the Genesis of Pancreatic Ductal Adenocarcinoma
    Collisson, Eric A.
    Trejo, Christy L.
    Silva, Jillian M.
    Gu, Shenda
    Korkola, James E.
    Heiser, Laura M.
    Charles, Roch-Philippe
    Rabinovich, Brian A.
    Hann, Byron
    Dankort, David
    Spellman, Paul T.
    Phillips, Wayne A.
    Gray, Joe W.
    McMahon, Martin
    [J]. CANCER DISCOVERY, 2012, 2 (08) : 685 - 693
  • [9] EGFR-Mediated Reactivation of MAPK Signaling Contributes to Insensitivity of BRAF-Mutant Colorectal Cancers to RAF Inhibition with Vemurafenib
    Corcoran, Ryan B.
    Ebi, Hiromichi
    Turke, Alexa B.
    Coffee, Erin M.
    Nishino, Michiya
    Cogdill, Alexandria P.
    Brown, Ronald D.
    Della Pelle, Patricia
    Dias-Santagata, Dora
    Hung, Kenneth E.
    Flaherty, Keith T.
    Piris, Adriano
    Wargo, Jennifer A.
    Settleman, Jeffrey
    Mino-Kenudson, Mari
    Engelman, Jeffrey A.
    [J]. CANCER DISCOVERY, 2012, 2 (03) : 227 - 235
  • [10] Mutations of the BRAF gene in human cancer
    Davies, H
    Bignell, GR
    Cox, C
    Stephens, P
    Edkins, S
    Clegg, S
    Teague, J
    Woffendin, H
    Garnett, MJ
    Bottomley, W
    Davis, N
    Dicks, N
    Ewing, R
    Floyd, Y
    Gray, K
    Hall, S
    Hawes, R
    Hughes, J
    Kosmidou, V
    Menzies, A
    Mould, C
    Parker, A
    Stevens, C
    Watt, S
    Hooper, S
    Wilson, R
    Jayatilake, H
    Gusterson, BA
    Cooper, C
    Shipley, J
    Hargrave, D
    Pritchard-Jones, K
    Maitland, N
    Chenevix-Trench, G
    Riggins, GJ
    Bigner, DD
    Palmieri, G
    Cossu, A
    Flanagan, A
    Nicholson, A
    Ho, JWC
    Leung, SY
    Yuen, ST
    Weber, BL
    Siegler, HF
    Darrow, TL
    Paterson, H
    Marais, R
    Marshall, CJ
    Wooster, R
    [J]. NATURE, 2002, 417 (6892) : 949 - 954