A review of kinases implicated in pancreatic cancer.
The current 5-year survival rate of pancreatic cancer is about 3% and the median survival less than 6 months because the chemotherapy and radiation therapy presently available provide only marginal benefit. Clearly, pancreatic cancer requires new therapeutic concepts. Recently, the kinase inhibitors imatinib and gefitinib, developed to treat chronic myelogenous leukaemia and breast cancer, respectively, gave very good results. Kinases are deregulated in many diseases, including cancer. Given that phosphorylation controls cell survival signalling, strategies targeting kinases should obviously improve cancer treatment. The purpose of this review is to summarize the present knowledge on kinases potentially usable as therapeutic targets in the treatment of pancreatic cancer. All clinical trials using available kinase inhibitors in monotherapy or in combination with chemotherapeutic drugs failed to improve survival of patients with pancreatic cancer. To detect kinases relevant to this disease, we undertook a systematic screening of the human kinome to define a 'survival kinase' catalogue for pancreatic cells. We selected 56 kinases that are potential therapeutic targets in pancreatic cancer. Preclinical studies using combined inhibition of PAK7, MAP3K7 and CK2 survival kinases in vitro and in vivo showed a cumulative effect on apoptosis induction. We also observed that these three kinases are rather specific of pancreatic cancer cells. In conclusion, if kinase inhibitors presently available are unfortunately not efficient for treating pancreatic cancer, recent data suggest that inhibitors of other kinases, involved more specifically in pancreatic cancer development, might, in the future, become interesting therapeutic targets.
Giroux
Valentin
V
INSERM U624, Stress Cellulaire, Parc Scientifique et Technologique de Luminy, Marseille Cedex 9, France.
Dagorn
Jean-Charles
JC
Iovanna
Juan L
JL
D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002986:Clinical Trials as Topic; D005260:Female; D006801:Humans; D008297:Male; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor