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Potent Activity of Ponatinib (AP24534) in Models of FLT3-Driven Acute Myeloid Leukemia and Other Hematologic Malignancies

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Potent Activity of Ponatinib (AP24534) in Models of FLT3-Driven Acute Myeloid Leukemia and Other Hematologic Malignancies Published OnlineFirst April 11, 2011; DOI: 10.1158/1535-7163.MCT-10-1044 Molecular Cancer Preclinical Development Therapeutics Potent Activity of Ponatinib (AP24534) in Models of FLT3-Driven Acute Myeloid Leukemia and Other Hematologic Malignancies Joseph M. Gozgit1, Matthew J. Wong1, Scott Wardwell1, Jeffrey W. Tyner2, Marc M. Loriaux2, Qurish K. Mohemmad1, Narayana I. Narasimhan1, William C. Shakespeare1, Frank Wang1, Brian J. Druker2, Tim Clackson1, and Victor M. Rivera1 Abstract Ponatinib (AP24534) is a novel multitargeted kinase inhibitor that potently inhibits native and mutant BCR- ABL at clinically achievable drug levels. Ponatinib also has in vitro inhibitory activity against a discrete set of kinases implicated in the pathogenesis of other hematologic malignancies, including FLT3, KIT, fibroblast growth factor receptor 1 (FGFR1), and platelet derived growth factor receptor a (PDGFRa). Here, using leukemic cell lines containing activated forms of each of these receptors, we show that ponatinib potently inhibits receptor phosphorylation and cellular proliferation with IC50 values comparable to those required for inhibition of BCR-ABL (0.3 to 20 nmol/L). The activity of ponatinib against the FLT3-ITD mutant, found in up þ þ to 30% of acute myeloid leukemia (AML) patients, was particularly notable. In MV4-11 (FLT3-ITD / ) but not À À RS4;11 (FLT3-ITD / ) AML cells, ponatinib inhibited FLT3 signaling and induced apoptosis at concentrations of less than 10 nmol/L. In an MV4-11 mouse xenograft model, once daily oral dosing of ponatinib led to a dose-dependent inhibition of signaling and tumor regression. Ponatinib inhibited viability of primary leukemic blasts from a FLT3-ITD positive AML patient (IC50 4 nmol/L) but not those isolated from 3 patients with AML expressing native FLT3. Overall, these results support the investigation of ponatinib in patients with FLT3-ITD–driven AML and other hematologic malignancies driven by KIT, FGFR1, or PDGFRa. Mol Cancer Ther; 10(6); 1028–35. Ó2011 AACR. Introduction ref. 2). Dysregulation of these RTKs, for example via genetic alterations that lead to the generation of fusion Ponatinib (AP24534) is an oral multitargeted tyrosine proteins or activating mutations, has been implicated in kinase inhibitor (TKI) that has been characterized pre- the pathogenesis of multiple hematologic malignancies viously for its ability to potently inhibit BCR-ABL (1–3). (4, 5). Importantly, ponatinib inhibits both native and mutant Translocations affecting the activity of FGFR1 and forms of BCR-ABL, including the T315I gatekeeper PDGFRa are found in a subset of rare myeloproliferative mutant that is refractory to all approved TKIs. Ponatinib neoplasms (ref. 6). Translocations involving the FGFR1 is currently being investigated in a pivotal phase 2 clinical gene and a range of other chromosome partners such as trial in patients with chronic myeloid leukemia (CML, the FGFR1OP2 gene are characteristic of 8p11 myelopro- NCT01207440, www.clinicaltrials.gov). We have pre- liferative syndrome which is an aggressive disease that viously shown that ponatinib exhibits potent in vitro can rapidly transform to acute myeloid leukemia (AML; inhibitory activity against a discrete subset of additional ref. 7). The FIP1L1-PDGFRa fusion protein is found in protein tyrosine kinases including members of the class approximately 10% to 20% of patients with chronic eosi- III/IV subfamily of receptor tyrosine kinases (RTK) FLT3, nophilic leukemia/idiopathic hypereosinophilia and it KIT, FGFR1 (fibroblast growth factor receptor 1), and has been reported that these patients respond well to platelet derived growth factor receptor a (PDGFRa; PDGFR inhibition (6). Activating mutations in KIT and FLT3 are found in AML. KIT mutations are less common and are found in specific cytogenetic subsets of AML with Authors' Affiliations: 1ARIAD Pharmaceuticals, Inc., Cambridge, Massa- 2 an overall frequency of 2% to 8% (8). Activating muta- chusetts; and Division of Hematology and Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, Oregon tions in FLT3 are the most common type of genetic Corresponding Author: Victor M. Rivera, ARIAD Pharmaceuticals, Inc., 26 alteration in AML, found in up to 30% of newly diag- Landsdowne Street, Cambridge, MA 02139. Phone: 617-494-0400; Fax: nosed patients (9). The majority of these mutations arise 617-494-8144; E-mail: [email protected] from an internal tandem duplication (ITD) in the juxta- doi: 10.1158/1535-7163.MCT-10-1044 membrane region of the receptor. Activating point muta- Ó2011 American Association for Cancer Research. tions in the kinase activation loop also occur, but with 1028 Mol Cancer Ther; 10(6) June 2011 Downloaded from mct.aacrjournals.org on September 25, 2021. © 2011 American Association for Cancer Research. Published OnlineFirst April 11, 2011; DOI: 10.1158/1535-7163.MCT-10-1044 Ponatinib Is a Potent Inhibitor of FLT3-ITD lower frequency. FLT3-ITD mutations have been asso- (PerkinElmer). Data are plotted as percent viability rela- ciated with a worse prognosis for AML patients, both in tive to vehicle-treated cells and the IC50 values (the terms of relapse and overall survival, when treated with concentration that causes 50% inhibition) are calculated standard therapy (9–11). using XLfit version 4.2.2 for Microsoft Excel. Data are AML is the most common myeloid disorder in adults, shown as mean (ÆSD) from 3 separate experiments, each which has the worst prognosis of all leukemias and lacks tested in triplicate. effective targeted therapies (12). FLT3-ITD has emerged as an attractive therapeutic target, and consequently a Immunoblot analysis number of small molecule TKIs with activity against To examine inhibition of RTK signaling, cells were FLT3 have now been developed. Many of these com- treated with ponatinib over a range of concentrations pounds have already been evaluated in clinical trials, for 1 hour. Cells were lysed in ice-cold SDS lysis buffer including CEP-701 (lestaurtinib), PKC412 (midostaurin), (0.06 mol/L Tris-HCL. 1% SDS, and 10% glycerol) and sunitinib, sorafenib, MLN-518 (tandutinib), and KW-2449 protein concentration was determined using a bicincho- (13, 14). Overall, however, most of these agents have ninic acid (BCA) protein assay (Thermo Scientific). Cel- shown relatively modest clinical activity and the effects lular lysates (50 mg) were resolved by electrophoresis and have not been durable, suggesting that first-generation transferred to nitrocellulose membranes using NuPage FLT3 inhibitors may have limited utility as single agents Novex reagents (Invitrogen). Membranes were immuno- (13–15). However, FLT3-ITD remains an attractive drug blotted with phosphorylated antibodies and then target and new inhibitors such as AC220 (16, 17) have exposed to Supersignal ELISA femto maximum sensitiv- begun to show promising clinical activity. ity substrate (Thermo Scientific) to generate a chemilu- We evaluated the cellular activity of ponatinib against minescent signal. Band intensity was quantified using FLT3, KIT, FGFR1, and PDGFRa in a panel of leukemic Quantity One 4.6.7 software (Bio-Rad). Membranes were cell lines that express these dysregulated RTKs to explore stripped with Restore Western Blot Stripping Buffer potential applications of ponatinib in hematologic malig- (Thermo Scientific) and immunoblotted with total protein nancies beyond BCR-ABL–driven CML. We further antibodies. The IC50 values were calculated by plotting assessed the potency and selectivity of ponatinib for percent phosphorylated protein in ponatinib-treated cells FLT3-ITD in primary leukemic blasts and the efficacy relative to vehicle-treated cells. of ponatinib in a FLT3-ITD–driven xenograft model. Apoptosis assays Materials and Methods For measurement of caspase activity, MV4-11 cells were seeded into black-walled 96-well plates at 1 Â 104 Cell lines, antibodies, and reagents cells per well for 24 hours and then treated with ponatinib MV4-11, RS4;11, Kasumi-1, and KG1 cells were for the indicated time-points. Apo-One Homogeneous obtained from the American Type Culture Collection, Caspase-3/7 Reagent (Promega) was added according and EOL1 cells were obtained from DSMZ. Further cell to the manufacturer’s protocol, and fluorescence was line authentication was not carried out by the authors. measured in the Wallac Victor microplate reader. To Cells were maintained and cultured according to stan- measure PARP cleavage, MV4-11 cells were plated in dard techniques at 37 C in 5% (v/v) CO2 using RPMI 6-well plates and, the following day, were treated for 24 1640 supplemented with 10% FBS (20% FBS for Kasumi-1 hours with ponatinib. At the end of treatment, cells were cells). The antibodies used included: phospho-PDGFRa, lysed with SDS buffer and immunoblotted to measure for PDGFRa, FLT3, FGFR1, and GAPDH from Santa Cruz both total PARP and cleaved PARP expression (Cell Biotechnology; STAT5, KIT, phospho-KIT, phospho- Signaling Technology). FGFR, and phospho-FLT3 from Cell Signaling Technol- ogy; phospho-STAT5 from BD Biosciences. Ponatinib was Subcutaneous xenograft model synthesized at ARIAD Pharmaceuticals, and sorafenib All animal experiments were carried out under a pro- and sunitinib were purchased from American Custom tocol approved by the Institutional Animal Care and Use Chemical Corporation. Stock solutions (10 mmol/L) in Committee. The MV4-11 human tumor xenograft efficacy dimethyl sulfoxide of the above compounds were pre- study was carried out by
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