RT Journal Article
SR Electronic
T1 A subset of metastatic pancreatic ductal adenocarcinomas depends quantitatively on oncogenic Kras/Mek/Erk-induced hyperactive mTOR signalling
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 647
OP 657
DO 10.1136/gutjnl-2014-307616
VO 65
IS 4
A1 Kong, Bo
A1 Wu, Weiwei
A1 Cheng, Tao
A1 Schlitter, Anna Melissa
A1 Qian, Chengjia
A1 Bruns, Philipp
A1 Jian, Ziying
A1 Jäger, Carsten
A1 Regel, Ivonne
A1 Raulefs, Susanne
A1 Behler, Nora
A1 Irmler, Martin
A1 Beckers, Johannes
A1 Friess, Helmut
A1 Erkan, Mert
A1 Siveke, Jens T
A1 Tannapfel, Andrea
A1 Hahn, Stephan A
A1 Theis, Fabian J
A1 Esposito, Irene
A1 Kleeff, Jörg
A1 Michalski, Christoph W
YR 2016
UL http://gut.bmj.com/content/65/4/647.abstract
AB Objective Oncogenic Kras-activated robust Mek/Erk signals phosphorylate to the tuberous sclerosis complex (Tsc) and deactivates mammalian target of rapamycin (mTOR) suppression in pancreatic ductal adenocarcinoma (PDAC); however, Mek and mTOR inhibitors alone have demonstrated minimal clinical antitumor activity.Design We generated transgenic mouse models in which mTOR was hyperactivated either through the Kras/Mek/Erk cascade, by loss of Pten or through Tsc1 haploinsufficiency. Primary cancer cells were isolated from mouse tumours. Oncogenic signalling was assessed in vitro and in vivo, with and without single or multiple targeted molecule inhibition. Transcriptional profiling was used to identify biomarkers predictive of the underlying pathway alterations and of therapeutic response. Results from the preclinical models were confirmed on human material.Results Reduction of Tsc1 function facilitated activation of Kras/Mek/Erk-mediated mTOR signalling, which promoted the development of metastatic PDACs. Single inhibition of mTOR or Mek elicited strong feedback activation of Erk or Akt, respectively. Only dual inhibition of Mek and PI3K reduced mTOR activity and effectively induced cancer cell apoptosis. Analysis of downstream targets demonstrated that oncogenic activity of the Mek/Erk/Tsc/mTOR axis relied on Aldh1a3 function. Moreover, in clinical PDAC samples, ALDH1A3 specifically labelled an aggressive subtype.Conclusions These results advance our understanding of Mek/Erk-driven mTOR activation and its downstream targets in PDAC, and provide a mechanistic rationale for effective therapeutic matching for Aldh1a3-positive PDACs.