Lessons from Tarceva in pancreatic cancer: where are we now, and how should future trials be designed in pancreatic cancer?
OBJECTIVE
The recent advances in the use of targeted therapy in pancreatic cancer are based on the knowledge of genetic alterations that occur during pancreatic carcinogenesis. We describe the repository of frequent alterations targeting tumour suppressor genes and oncogenes. We focus our attention on the epidermal growth factor receptor signalling pathway, which can be activated through different alterations and seems to play a central role in the cell transformation. Multiple targeted drugs have been developed against different partners of this network trying to improve the treatment of pancreatic cancer patients.


RESULTS
Tarceva has obtained approval in the USA and Europe for metastatic pancreatic cancer with a modest increase of median survival and a 6% increase in 1-year survival rates, suggesting that only a small fraction of patients truly benefit from it. The comparison with lung and colon cancer suggests that Kras mutations could be a predictive marker of resistance. Other promising drugs targeting different partners of the epidermal growth factor receptor signalling pathway could play a synergistic role with Tarceva as inhibitors of mTOR, mitogen-activated protein kinase kinase 1, and nuclear factor-kappaB or can directly turn down Ras.


CONCLUSIONS
The biology of the epidermal growth factor receptor, mitogen-activated protein kinase, PI3K/mTOR network suggests that a combination of drugs targeting simultaneously different partners should improve survival.
Paris Descartes University, France. pierre.laurent-puig@univ-paris5.fr
Pierre
P
Laurent-Puig
Julien
J
Taieb
D002986:Clinical Trials as Topic; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D012107:Research Design / Q000639:trends*
D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors