title: The novel tyrosine kinase inhibitor EXEL-0862 induces apoptosis in human FIP1L1-PDGFR-alpha-expressing cells through caspase-3-mediated cleavage of Mcl-1.
abstract: The FIP1-like-1 (FIP1L1)-platelet-derived growth factor receptor-alpha (FIP1L1-PDGFR-alpha) fusion kinase causes hypereosinophilic syndrome (HES) in a defined subset of patients. Imatinib mesylate is a potent inhibitor of ABL but also of PDGFR-alpha, 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-alpha-expressing cell lines and in cells from a patient with HES harboring the FIP1L1-PDGFR-alpha gene. EXEL-0862 inhibited the proliferation of EOL-1 and imatinib-resistant T674I FIP1L1-PDGFR-alpha-expressing cells and resulted in potent inhibition of the phosphorylation of PDGFR-alpha 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-alpha-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-alpha-positive HES.
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: J
authors.initials: J
authors.lastname: Pan
authors.forename: A
authors.initials: A
authors.lastname: Quintás-Cardama
authors.forename: T
authors.initials: T
authors.lastname: Manshouri
authors.forename: F J
authors.initials: FJ
authors.lastname: Giles
authors.forename: P
authors.initials: P
authors.lastname: Lamb
authors.forename: A
authors.initials: A
authors.lastname: Tefferi
authors.forename: J
authors.initials: J
authors.lastname: Cortes
authors.forename: H
authors.initials: H
authors.lastname: Kantarjian
authors.forename: S
authors.initials: S
authors.lastname: Verstovsek
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D053148:Caspase 3 / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D017681:Hypereosinophilic Syndrome / Q000188:drug therapy* / Q000473:pathology; D000068877:Imatinib Mesylate; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion; D010879:Piperazines / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D020796:Receptor, Platelet-Derived Growth Factor alpha; D014407:Tumor Cells, Cultured; D039221:mRNA Cleavage and Polyadenylation Factors
chemical_list: D001549:Benzamides; D004791:Enzyme Inhibitors; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D039221:mRNA Cleavage and Polyadenylation Factors; D000068877:Imatinib Mesylate; C479819:FIP1L1-PDGFRA fusion protein, human; D011505:Protein-Tyrosine Kinases; D020796:Receptor, Platelet-Derived Growth Factor alpha; D053148:Caspase 3