1. ¹Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2. ²Department of Pathophysiology, Sun Yat-sen University Medical School, Guangzhou, PR China
3. ³Exelixis Inc., South San Francisco, CA, USA
4. ⁴Division of Hematology, Mayo Clinic College of Medicine, Rochester, MN, USA

Correspondence: Dr S Verstovsek, Department of Leukemia, UT MD Anderson Cancer Center, Unit 428, 1515 Holcombe Blvd, Houston, TX 77030, USA. E-mail: sverstov@mdanderson.org

Received 18 October 2006; Revised 14 March 2007; Accepted 20 March 2007; Published online 10 May 2007.

Abstract

The FIP1-like-1 (FIP1L1)-platelet-derived growth factor receptor-alpha (FIP1L1-PDGFR-) fusion kinase causes hypereosinophilic syndrome (HES) in a defined subset of patients. Imatinib mesylate is a potent inhibitor of ABL but also of PDGFR-, and has been associated with durable hematologic responses in patients with HES. However, development of mutations in the tyrosine kinase domain may hamper the activity of tyrosine kinase inhibitors (TKIs), which suggests that novel agents are warranted to prevent or overcome resistance. We evaluated the efficacy of the novel TKI EXEL-0862 in FIP1L1-PDGFR--expressing cell lines and in cells from a patient with HES harboring the FIP1L1-PDGFR- gene. EXEL-0862 inhibited the proliferation of EOL-1 and imatinib-resistant T674I FIP1L1-PDGFR--expressing cells and resulted in potent inhibition of the phosphorylation of PDGFR- and downstream proteins STAT3 and Erk1/2, both in vitro and ex vivo. Moreover, EXEL-0862 induced apoptotic death in EOL-1 cells and imatinib-resistant T674I FIP1L1-PDGFR--expressing cells, and resulted in significant downregulation of the antiapoptotic protein Mcl-1 through a caspase-dependent mechanism. Our data establish EXEL-0862 as a solid candidate for the targeted treatment of patients with FIP1L1-PDGFR--positive HES.