Sorafenib inhibits many kinase mutations associated with drug-resistant gastrointestinal stromal tumors.
Sorafenib has substantial clinical activity as third- or fourth-line treatment of imatinib- and sunitinib-resistant gastrointestinal stromal tumors (GIST). Because sorafenib targets both angiogenesis-related kinases (VEGFR) 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 four GIST cell lines, three of which are imatinib resistant. In our in vitro studies, we determined that sorafenib inhibited imatinib-resistant 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 IC(50)). 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.
Division of Hematology/Oncology, Department of Medicine, Portland VA Medical Center and OHSU Knight Cancer Institute, Oregon Health & Science University, R&D-19 3710 U.S. Veterans Hospital Road, Portland, OR 97239, USA. Heinrich@ohsu.edu
Michael C
MC
Heinrich
Adrian
A
Marino-Enriquez
Ajia
A
Presnell
Rachel S
RS
Donsky
Diana J
DJ
Griffith
Arin
A
McKinley
Janice
J
Patterson
Takahiro
T
Taguchi
Cher-Wei
CW
Liang
Jonathan A
JA
Fletcher
D001549:Benzamides; D001557:Benzenesulfonates / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D020128:Inhibitory Concentration 50; D009154:Mutation; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D000077157:Sorafenib
D001549:Benzamides; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D009536:Niacinamide; D000068877:Imatinib Mesylate; D000077157:Sorafenib; D011494:Protein Kinases; D019009:Proto-Oncogene Proteins c-kit