Sorafenib Inhibits Many Kinase Mutations Associated with Drug-Resistant Gastrointestinal Stromal Tumors
Menée in vitro, cette étude met en évidence un mécanisme rendant compte de l'activité du sorafenib dans le traitement d'une tumeur stromale gastrointestinale ayant développé une résistance à l'imatinib et au sunitinib
Sorafenib has substantial clinical activity as third- or fourth-line treatment of imatinib- and sunitinib-resistant GI stromal tumors (GIST). Because sorafenib targets both angiogenesis-related kinases (VEGFRs) and the pathogenetic kinases found in GIST (KIT or PDGFRA), the molecular basis for sorafenib efficacy in this setting remains unknown. We sought to determine the spectrum of activity of sorafenib against different mutant kinases associated with drug-sensitive and drug-resistant GIST. We compared the activity of imatinib and sorafenib against transiently expressed mutant forms of KIT and PDGFRA, including various secondary mutations that have been identified in imatinib-resistant or sunitinib-resistant GISTs. We also examined these drugs against 4 GIST cell lines, 3 of which are imatinib resistant. In our in vitro studies, we determined that sorafenib inhibited imatinib-resistance mutations in exons encoding the ATP/drug binding pocket, and in exons encoding the activation loop, with the exception of substitutions at KIT codon D816 and PDGFRA codon 842. Notably our data indicate that sorafenib is more effective than imatinib or sunitinib for inhibiting the kinase activity of drug resistant KIT mutants (as assessed by biochemical IC50). We hypothesize that a major determinant of the efficacy of sorafenib for treatment of advanced GIST is the activity of this agent against KIT or PDGFRA mutant kinases. These results have implications for the further development of treatments for drug-resistant GIST.
http://mct.aacrjournals.org/content/early/2012/06/02/1535-7163.MCT-12-0223.abstract