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Gut. 2013 Oct;62(10):1415-24. doi: 10.1136/gutjnl-2012-302039. Epub 2012 Jul 6.

A systematic approach to therapeutic target selection in oesophago-gastric cancer.

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1
MRC Cancer Cell Unit, Hutchison-MRC Research Centre, Cambridge, UK.

Abstract

OBJECTIVE:

The success of personalised therapy depends on identification and inhibition of the oncogene(s) on which that tumour is dependent. We aimed to determine whether a receptor tyrosine kinase (RTK) array could be used to select the most effective therapeutic strategies in molecularly heterogeneous oesophago-gastric adenocarcinomas.

DESIGN:

Gene expression profiling from oesophago-gastric tumours (n=75) and preinvasive stages (n=57) identified the active signalling pathways, which was confirmed using immunohistochemistry (n=434). RTK arrays on a cell line panel (n=14) determined therapeutic targets for in vitro cytotoxic testing. Feasibility of this personalised approach was tested in tumour samples (n=46).

RESULTS:

MAPK was the most frequently activated pathway (32/75 samples (42.7%)) with progressive enrichment in preinvasive disease stages (p<0.05) and ERK phosphorylation in 148/434 (34.3%) independent samples. Cell lines displayed a range of RTK activation profiles. When no RTKs were activated, tyrosine kinase inhibitors (TKIs) and a Mek inhibitor were not useful (MKN1). In lines with a dominant phosphorylated RTK (OE19, MKN45 and KATOIII), selection of this TKI or Mek in nM concentrations induced cytotoxicity and inhibited Erk and Akt phosphorylation. In cells lines with complex activation profiles (HSC39 and OE33), a combination of TKIs or Mek inhibition (in nM concentrations) was necessary for cytotoxicity and inhibition of Erk and Akt phosphorylation. Human tumours demonstrated diverse activation profiles and 65% of cases had two or more active RTKs.

CONCLUSIONS:

The MAPK pathway is commonly activated in oesophago-gastric cancer following activation of a variety of RTKs. Molecular phenotyping can inform a rational choice of targeted therapy.

KEYWORDS:

Barrett's oesophagus; MAPK pathways; Oesophageal adenocarcinoma; adenocarcinoma; biostatistics; cancer genetics; cell signalling; gastro-oesophageal reflux disease; oesophageal cancer; oncogene addiction; receptor tyrosine kinases; small molecular inhibitors

PMID:
22773546
DOI:
10.1136/gutjnl-2012-302039
[Indexed for MEDLINE]
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