Crenolanib Inhibits the Drug-Resistant PDGFRA D842V Mutation Associated with Imatinib-Resistant Gastrointestinal Stromal Tumors

• Published in: Clinical cancer research Vol. 18; no. 16; pp. 4375 - 4384
• Main Authors: HEINRICH, Michael C, GRIFFITH, Diana, MCKINLEY, Arin, PATTERSON, Janice, PRESNELL, Ajia, RAMACHANDRAN, Abhijit, DEBIEC-RYCHTER, Maria
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.08.2012
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - pharmacology; Benzamides; Benzimidazoles - pharmacology; Biological and medical sciences; Cell Line, Tumor; CHO Cells; Cricetinae; Drug Resistance, Neoplasm - genetics; Enzyme Activation - drug effects; Gastroenterology. Liver. Pancreas. Abdomen; Gastrointestinal Stromal Tumors - genetics; Humans; Imatinib Mesylate; Inhibitory Concentration 50; Medical sciences; Mutation; Pharmacology. Drug treatments; Piperazines - pharmacology; Piperidines; Protein Kinase Inhibitors - pharmacology; Pyrimidines - pharmacology; Receptor, Platelet-Derived Growth Factor alpha - antagonists & inhibitors; Receptor, Platelet-Derived Growth Factor alpha - genetics; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors; Antineoplastic agent; Platelet derived growth factor receptor A; Imatinib; Treatment resistance; Enzyme; Tyrosine kinase inhibitor; Transferases; Enzyme inhibitor; Malignant tumor; Gastrointestinal stromal tumor; Digestive diseases; Intestinal disease; Genetics; Mutation; Protein-tyrosine kinase; Cancer; Gastric disease
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-12-0625

To determine the potential of crenolanib, a potent inhibitor of PDGFRA, to treat malignancies driven by mutant PDGFRA. The biochemical activity of crenolanib was compared with imatinib using a panel of PDGFRA-mutant kinases expressed in several different cell line models, including primary gastrointestinal stromal tumors (GIST) cells. The antiproliferative activity of crenolanib was also studied in several cell lines with PDGFRA-dependent growth. Crenolanib was significantly more potent than imatinib in inhibiting the kinase activity of imatinib-resistant PDGFRA kinases (D842I, D842V, D842Y, DI842-843IM, and deletion I843). For example, crenolanib was 135-fold more potent than imatinib against D842V in our isogenic model system, with an IC(50) of approximately 10 nmol/L. The relative potency of crenolanib was further confirmed in BaF3 and primary GIST cells expressing PDGFRA D842V. In contrast, imatinib was at least 10-fold more potent than crenolanib in inhibiting the V561D mutation. For all other tested PDGFRA mutations, crenolanib and imatinib had comparable potency. Crenolanib is a potent inhibitor of imatinib-resistant PDGFRA kinases associated with GIST, including the PDGFRA D842V mutation found in approximately 5% of GISTs. The spectrum of activity of crenolanib suggests that this drug is a type I inhibitor (inhibitor of activated conformation of kinase). Based in part on these results, a phase II clinical study of this agent to treat GIST with the PDGFRA D842V mutation has been initiated.