title: A screening-based approach to circumvent tumor microenvironment-driven intrinsic resistance to BCR-ABL+ inhibitors in Ph+ acute lymphoblastic leukemia.
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.
authors.affiliation: 1Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Harpreet
authors.initials: H
authors.lastname: Singh
authors.forename: Anang A
authors.initials: AA
authors.lastname: Shelat
authors.forename: Amandeep
authors.initials: A
authors.lastname: Singh
authors.forename: Nidal
authors.initials: N
authors.lastname: Boulos
authors.forename: Richard T
authors.initials: RT
authors.lastname: Williams
authors.forename: R Kiplin
authors.initials: RK
authors.lastname: Guy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors*; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D010641:Phenotype; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology* / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D059016:Tumor Microenvironment / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D047428:Protein Kinase Inhibitors; D016044:Fusion Proteins, bcr-abl
keywords: cancer and cancer drugs; cell-based assays; kinases; phenotypic drug discovery