[Gastrointestinal stromal tumors: molecular aspects and therapeutic implications].
Approximately 90 % of gastrointestinal tumors (GISTs) harbor an activating mutation in KIT or PDGFR alpha oncogene known to confer imatinib sensitivity. Imatinib is a tyrosine kinase inhibitor of KIT and PDGFRs that yields a 6-months progression-free survival (PFS) rate of 80 % in patients with advanced GISTs. Several studies have shown that response to imatinib in GIST patients mainly depends on the mutational status of KIT or PDGFR alpha. Moreover, most if not all patients treated with imatinib for advanced GIST will secondarily develop progressive disease under treatment. In the majority of cases, such progressions are the result of acquired resistance due to occurrence of secondary C-KIT mutations; especially for GIST with primary exon 11 mutations. Sunitinib is another approved drug and an inhibitor of multiple tyrosine kinases including KIT, PDGFR alpha as well as PDGFR beta and VEGFRs which are associated with angiogenesis. Sunitinib, in phase II and III trials was associated with durable clinical benefit in nearly 25 % of patients with advanced GIST resistant/intolerant to imatinib. Clearly, a better knowledge of the molecular mechanisms underlying the resistance to imatinib as well as the development of a new class of broad-spectrum tyrosine kinase inhibitors may allow in the near future new individualized therapeutic strategies for GISTs patients.
Italiano
Antoine
A
Centre Antoine-Lacassagne, Département d'oncologie médicale, Nice, France.
Bui
Binh
B
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D001557:Benzenesulfonates / Q000627:therapeutic use; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000627:therapeutic use*; D009154:Mutation; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D009536:Niacinamide / Q000031:analogs & derivatives / Q000627:therapeutic use; D009841:Oligonucleotides; D010671:Phenylurea Compounds; D010793:Phthalazines / Q000627:therapeutic use; D010879:Piperazines / Q000627:therapeutic use*; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D011725:Pyridines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use*; D011758:Pyrroles / Q000627:therapeutic use*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors / Q000235:genetics; D000077157:Sorafenib; D019311:Staurosporine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000077210:Sunitinib; D013844:Thiazoles / Q000627:therapeutic use
D000970:Antineoplastic Agents; D001549:Benzamides; D001557:Benzenesulfonates; D007211:Indoles; D009363:Neoplasm Proteins; D009841:Oligonucleotides; D010671:Phenylurea Compounds; D010793:Phthalazines; D010879:Piperazines; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D011758:Pyrroles; D013844:Thiazoles; D009536:Niacinamide; C404768:vatalanib; D000068877:Imatinib Mesylate; D000077157:Sorafenib; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; C498826:nilotinib; C519562:imetelstat; D019311:Staurosporine; C059539:midostaurin; C526575:masitinib; D000077210:Sunitinib