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Activity of Dasatinib, a Dual SRC/ABL Kinase Inhibitor, and IPI-504, a Heat Shock Protein 90 Inhibitor, against Gastrointestinal Stromal Tumor–Associated PDGFRA^D842V Mutation

Authors' Affiliations: Departments of ¹ Human Genetics, ² Pathology, and ³ General Medical Oncology, K.U. Leuven, and ⁴ VIB Department of Molecular and Developmental Genetics, VIB, Leuven, Belgium

Requests for reprints: Maria Debiec-Rychter, Department of Human Genetics, University of Leuven, O&N Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. Phone: 32-16-347218; Fax: 32-16-346210; E-mail: Maria.Debiec-Rychter{at}med.kuleuven.be.

Purpose: Activating mutations in platelet-derived growth factor receptor- (PDGFRA) have been reported in 5% to 10% of patients with gastrointestinal stromal tumors (GIST). Imatinib efficiently inhibits the juxtamembrane PDGFRA mutations, whereas many tyrosine kinase domain activation loop PDGFRA mutations confer primary resistance to imatinib. In this study, we compared the efficacy of second-line tyrosine kinase inhibitors such as dasatinib, sorafenib, and nilotinib against two GIST-related PDGFRA mutants, PDGFRA^D842V and PDGFRA^DIM842-844. In addition, we sought to investigate the inhibitory effect of the heat shock protein 90 inhibitor, IPI-504, on these mutants.

Experimental Design: Primary imatinib-resistant tumor cells and cell lines expressing imatinib-resistant PDGFRA^D842V or imatinib-sensitive PDGFRA^DIM842-844 mutants were treated with different concentrations of dasatinib, sorafenib, nilotinib, and IPI-504. The effect of treatment on proliferation, survival, and signaling was determined.

Results: All inhibitors tested exhibited a high efficacy toward the PDGFRA^DIM842-844 mutant. In contrast, ex vivo and in vitro assays revealed that only dasatinib potently inhibited the PDGFRA^D842V isoform with an IC₅₀ value of 62 nmol/L. Sorafenib and nilotinib were significantly less efficacious against this mutation, inhibiting the PDGFRA kinase activity at >1,000 and >5,000 nmol/L, and suppressing the proliferation of the cells expressing the PDGFRA^D842V mutant with an IC₅₀ value of 239 and 1,310 nmol/L, respectively. IPI-504 treatment potently inhibited PDGFRA kinase activity by inducing the degradation of PDGFRA^D842V and PDGFRA^DIM842-844 at 256 and 182 nmol/L, respectively.

Conclusions: Treatment with dasatinib or the heat shock protein 90 inhibitor IPI-504 may provide a therapeutic alternative for GIST patients whose tumors carry the imatinib-resistant PDGFRA^D842V mutant isoform.