Ras in digestive oncology: from molecular biology to clinical implications.
OBJECTIVE
The modalities of Ras mutation detection, its role as a predictive biomarker, mechanisms of wild-type Ras activation, and the role of Ras-directed targeted therapies will be discussed mainly in colorectal cancer.


RESULTS
RAS genotype is generally considered to be highly concordant between primary colorectal tumours and metastases. However, recent data show significant discordance between primary tumours and specific metastatic sites, but also heterogeneity within primary tumours. Moreover, the mechanisms of Ras activation expand far beyond mutations through altered expression or function of physiological Ras activators and inhibitors. Accordingly, genomic signatures of Ras or epidermal growth factor receptor (EGFR) activation are being developed and are potential predictive biomarkers of response to anti-EGFR antibodies. Finally, several recent clinical trials targeting Ras or its downstream signalling with statins or Raf inhibitors have shown promising activity in chemorefractory metastatic colorectal cancer.


CONCLUSIONS
RAS mutation remains an important biomarker predicting response to anti-EGFR therapies and perhaps clinical outcomes after surgery for metastatic colorectal cancer, but new techniques including genomic signatures need to be validated to take into account the complexity of Ras activation. The importance of Ras signalling as a therapeutic target has recently been outlined by successful clinical trials with Raf inhibitors.
aDepartment of Medicine, Digestive Oncology Unit, Institut Jules Bordet, Université Libre de Bruxelles bDepartment of Gastroenterology, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
Nicolas
N
Charette
Caroline
C
Vandeputte
Peter
P
Stärkel
D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D011905:Genes, ras; D005838:Genotype; D006801:Humans; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D019908:Proto-Oncogene Proteins c-raf / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D018631:ras Proteins / Q000502:physiology*
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors; D019908:Proto-Oncogene Proteins c-raf; D018631:ras Proteins