A systematic approach to therapeutic target selection in oesophago-gastric cancer
- Anna L Paterson1,
- Nicholas B Shannon1,
- Pierre Lao-Sirieix1,
- Chin-Ann J Ong1,
- Christopher J Peters1,
- Maria O'Donovan1,2,
- Rebecca C Fitzgerald1
- 1MRC Cancer Cell Unit, Hutchison-MRC Research Centre, Cambridge, UK
- 2Department of Pathology, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
- Correspondence to Dr Rebecca C Fitzgerald, MRC Cancer Cell Unit, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ, UK;
Contributors ALP and NBS designed the study, performed experiments, analysed data and wrote the manuscript; PLS analysed data and wrote the manuscript; CAJO performed experiments; CJP performed experiments; MoD performed experiments; RCF designed the study and wrote the manuscript.
- Revised 7 June 2012
- Accepted 9 June 2012
- Published Online First 6 July 2012
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.
- Oesophageal adenocarcinoma
- oncogene addiction
- small molecular inhibitors
- receptor tyrosine kinases
- MAPK pathways
- oesophageal cancer
- cell signalling
- Barrett's oesophagus
- cancer genetics
- gastro-oesophageal reflux disease
Funding This work was supported by an MRC core grant, Cambridge Experimental Cancer Medicine Centre, NIHR Cambridge Biomedical Research Centre and a Coutts-Trotter studentship from Trinity College, Cambridge.
Competing interests None.
Ethics approval Ethics approval was provided by LREC Cambridgeshire.
Provenance and peer review Not commissioned; externally peer reviewed.