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

Anna L Paterson1, Nicholas B Shannon, Pierre Lao-Sirieix

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

Gut
|July 10, 2012
PubMed
Abstract

Insights

Personalized therapy for oesophago-gastric cancer requires identifying oncogene dependencies. Receptor tyrosine kinase (RTK) arrays can guide targeted therapy selection by revealing active signaling pathways in tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacogenomics

Background:

  • Personalized therapy success hinges on identifying and inhibiting tumor-specific oncogenes.
  • Oesophago-gastric adenocarcinomas are molecularly heterogeneous, necessitating tailored treatment strategies.
  • Receptor tyrosine kinases (RTKs) play a crucial role in cancer signaling pathways.

Purpose of the Study:

  • To evaluate the utility of a receptor tyrosine kinase (RTK) array in selecting effective therapeutic strategies for oesophago-gastric adenocarcinomas.
  • To correlate RTK activation profiles with pathway dependencies and potential drug responses.

Main Methods:

  • Gene expression profiling and immunohistochemistry were used to identify active signaling pathways in oesophago-gastric tumors and preinvasive lesions.
  • RTK arrays were employed on a cell line panel to determine therapeutic targets for in vitro cytotoxic testing.
  • The feasibility of a personalized, RTK-driven therapeutic approach was assessed in patient tumor samples.

Main Results:

  • The MAPK pathway was frequently activated (42.7%) in tumours, with enrichment in preinvasive stages.
  • RTK activation profiles varied across cell lines; targeted inhibitors were effective only when specific RTKs were activated.
  • Complex RTK activation patterns in cell lines and human tumors (65% with ≥2 active RTKs) required combination therapies for efficacy.

Conclusions:

  • The MAPK pathway is commonly activated in oesophago-gastric cancer via diverse RTK activation.
  • Molecular phenotyping using RTK arrays enables rational selection of targeted therapies.
  • Personalized treatment strategies can be informed by comprehensive RTK profiling.
Keywords:
Barrett's oesophagusMAPK pathwaysOesophageal adenocarcinomaadenocarcinomabiostatisticscancer geneticscell signallinggastro-oesophageal reflux diseaseoesophageal canceroncogene addictionreceptor tyrosine kinasessmall molecular inhibitors

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