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A Screening-Based Approach to Circumvent Tumor Microenvironment

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A Screening-Based Approach to Circumvent Tumor Microenvironment JBXXXX10.1177/1087057113501081Journal of Biomolecular ScreeningSingh et al. 501081research-article2013 Original Research Journal of Biomolecular Screening 2014, Vol 19(1) 158 –167 A Screening-Based Approach to © 2013 Society for Laboratory Automation and Screening DOI: 10.1177/1087057113501081 Circumvent Tumor Microenvironment- jbx.sagepub.com Driven Intrinsic Resistance to BCR-ABL+ Inhibitors in Ph+ Acute Lymphoblastic Leukemia Harpreet Singh1,2, Anang A. Shelat3, Amandeep Singh4, Nidal Boulos1, Richard T. Williams1,2*, and R. Kiplin Guy2,3 Abstract Signaling by the BCR-ABL fusion kinase drives Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myelogenous leukemia (CML). Despite their clinical activity in many patients with CML, the BCR-ABL kinase inhibitors (BCR-ABL-KIs) imatinib, dasatinib, and nilotinib provide only transient leukemia reduction in patients with Ph+ ALL. While host-derived growth factors in the leukemia microenvironment have been invoked to explain this drug resistance, their relative contribution remains uncertain. Using genetically defined murine Ph+ ALL cells, we identified interleukin 7 (IL-7) as the dominant host factor that attenuates response to BCR-ABL-KIs. To identify potential combination drugs that could overcome this IL-7–dependent BCR-ABL-KI–resistant phenotype, we screened a small-molecule library including Food and Drug Administration–approved drugs. Among the validated hits, the well-tolerated antimalarial drug dihydroartemisinin (DHA) displayed potent activity in vitro and modest in vivo monotherapy activity against engineered murine BCR-ABL-KI–resistant Ph+ ALL. Strikingly, cotreatment with DHA and dasatinib in vivo strongly reduced primary leukemia burden and improved long-term survival in a murine model that faithfully captures the BCR-ABL-KI–resistant phenotype of human Ph+ ALL. This cotreatment protocol durably cured 90% of treated animals, suggesting that this cell- based screening approach efficiently identified drugs that could be rapidly moved to human clinical testing. Keywords phenotypic drug discovery, cancer and cancer drugs, cell-based assays, kinases Introduction 1Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA Targeted BCR-ABL inhibition with imatinib has improved 2 1 Integrated Program in Biomedical Sciences, University of Tennessee outcome for chronic myelogenous leukemia (CML). Health Science Center, Memphis, TN, USA However, the situation is starkly different for pediatric and 3Department of Chemical Biology and Therapeutics, St. Jude Children’s adult Philadelphia chromosome–positive acute lymphoblas- Research Hospital, Memphis, TN, USA 4 tic leukemia (Ph+ ALL).2 While continuous BCR-ABL Department of Medicine, Kings County Hospital Center, Brooklyn, NY, inhibition therapy—using imatinib, nilotinib, or dasatinib— USA *Current address: Puma Biotechnology, Inc., Los Angeles, CA potently kills Ph+ ALL cells in vitro, these drugs induce only transient remissions in patients with Ph+ ALL, ultimately Received Apr 10, 2013, and in revised form May 31, 2013. Accepted for allowing relapse and giving poor long-term outcomes. publication Jul 20, 2013. Although additional chemotherapy and hematopoietic stem Supplementary material for this article is available on the Journal of cell transplantation (HSCT) improve the remission rate in Biomolecular Screening Web site at http://jbx.sagepub.com/supplemental. Ph+ ALL patients, relapses remain common,3 with an 18- to 24-month survival rate of 64% and an even worse relapse- Corresponding Author: free survival rate.3 Differences in primary responses to BCR- R. Kiplin Guy, PhD, Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, ABL kinase inhibitors (BCR-ABL-KIs) in patients with Ph+ Memphis, TN 38105-3678, USA. ALL and CML remain poorly understood and cannot be Email: [email protected] Downloaded from jbx.sagepub.com by guest on December 19, 2013 Singh et al. 159 attributed solely to mutations in the ABL kinase domain 95% viability at 24 h), PCR genotyping to confirm Arf –/– sta- (BCR-ABLMUTANTS).4 tus, mycoplasma testing (negative by Takara Bio Mycoplasma We previously developed a murine leukemia model of PCR assay [Clontech, Madison, WI]), sequence verification Ph+ ALL, using primary, polyclonal Arf –/– p185BCR-ABL of the BCR-ABL allele, and in vitro dasatinib potency luciferase-expressing (Luc+) leukemia-initiating pre–B confirmation. cells (LICs), which captures key genetic features of human The maximum DMSO concentration tolerated by LICs Ph+ ALL (i.e., BCR-ABL expression and CDKN2A dele- in culture was determined to be 0.2% (by volume) and was tion) and enables in vivo luminescent imaging to monitor maintained at ≤0.1% (by volume) in all subsequent work. response to therapy.5 Such BCR-ABLWT LICs retain pheno- LICs were plated in 384-well microplates at a cellular den- typic and signaling properties essential for suspended leu- sity of 5 × 104 per milliliter (1250 LICs per well in 25 µL kemic blasts to interact with the surrounding host BCM10) and confirmed to give exponential growth during environment6 not typically present in established leukemic the first 72 h (Suppl. Fig. S1). To select assay reagents, cell lines and remain responsive to cytokines implicated in three high-throughput screening (HTS) relevant cellular murine pre–B-cell development both in vitro and in vivo.6 assays were evaluated according to the manufacturer’s These polyclonal BCR-ABLWT LICs can very efficiently instructions (see Suppl. Fig. S3). The luminescent CTG initiate leukemias in syngeneic, immune-competent mice.6 (CellTiter-Glo; Promega, Madison, WI) assay, which moni- In “recipient” host mice engrafted with these LICs, residual tors cellular adenosine triphosphate (ATP) content, accu- BCR-ABLWT cells5 evade treatment with BCR-ABL inhibi- rately detected a low number of LICs, producing results tors, paralleling what is seen in human Ph+ ALL patients.4 comparable to those obtained by flow cytometry, and pro- BCR-ABL kinase domain (KD) mutations, including BCR- vided ease of use in HTS (no prolonged incubation step ABLT315I (resistant to imatinib, dasatinib, and nilotinib), required between reagent addition and assay readout). emerge only after long-term exposure to BCR-ABL-KIs.5,7 In When carried out after 72 h, the CTG assay had a 10,000- contrast to the in vivo setting, BCR-ABLWT murine and human fold dynamic range, had low signal variance (Z′ = 0.9 in cells are quite sensitive to BCR-ABL-KIs in vitro.8 This dis- semi-automated mode and Z′ = 0.8 in fully automated parity between in vitro and in vivo sensitivity implicates the mode), displayed minimal drift or edge effects, and had host microenvironment in attenuating the therapeutic response robust interplate and interday reproducibility. to BCR-ABL kinase inhibition. We previously reported that common γ chain receptor host cytokines modulate primary imatinib resistance,6 and other host-derived growth factors Forward Cytokine Phenotypic Screen 9–11 have been shown to attenuate BCR-ABL kinase inhibition. Lyophilized murine and human recombinant cytokines (R&D Currently, no consensus exists on the relative importance of Systems, Minneapolis, MN) were diluted with 1 mg/mL host cytokines or growth factors that attenuate the cellular bovine serum albumin (BSA) in sterile phosphate-buffered responses to BCR-ABL–targeted agents. saline (PBS) to a final concentration of 20 µg/mL and stored at We used a naive screening approach to identify interleukin 4 °C. Antileukemia drugs, BCR-ABL-KIs, and non–BCR- (IL)–7 as the most potent among candidate host growth factors ABL–specific KIs (LC labs; Sigma, St. Louis, MO) were solu- in inducing resistance to BCR-ABL-KIs in Ph+ ALL. bilized in DMSO to obtain 10-mM stock concentrations. Following on that study, we used a repurposing screen of exist- Subsequent serial titrations were prepared using DMSO in 0.5- ing drugs and clinical candidates to identify drugs that blocked WT mL vials or 384-well drug master plates and stored at –20 °C. proliferation of BCR-ABL LICs cultured with murine IL-7. To study the impact of murine cytokines on dasatinib This study identified both the majority of known antileukemic action, LIC stocks containing different concentrations of drugs and a few novel agents that could overcome cytokine- candidate cytokines were prepared in multichannel sterile dependent cell survival signaling. Testing of combinations of reservoirs and plated into 384-well plates. Drug delivery to these validated hits with dasatinib revealed that the antimalar- cell suspensions was accomplished with a V & P Scientific ial drug dihydroartemisinin (DHA) provides strong synergy (San Diego, CA) pin tool (Suppl. Table S1). For murine- with BCR-ABL-KIs against Ph+ ALL cells responding to the human comparisons, human SUP-B15 Ph+ ALL cells tumor microenvironment. When used in vivo, DHA-dasatinib (DSMZ cell culture collection, Liebniz, Germany) in combination therapy eradicates dasatinib-refractory leukemia McCoy’s media containing 20% fetal calf serum and peni- in vivo, providing near-complete long-term survival. cillin/streptomycin (Invitrogen, Carlsbad, CA) were plated at 12,500 cells in 25 µL/well in black clear-bottom 384-well Materials and Methods microplates. Drugs were transferred by pin transfer. After a Development of LIC-Based Screening Assay 72-h incubation at 37 °C, 20% (by volume) MTS assay reagent (CellTiter 96 Aqueous One Solution; Promega)
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