A screening-based approach to circumvent tumor microenvironment-driven intrinsic resistance to BCR-ABL+ inhibitors in Ph+ acute lymphoblastic leukemia

Harpreet Singh, Anang A. Shelat, Amandeep Singh, Nidal Boulos, Richard T. Williams, R. Kiplin Guy

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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.

Original languageEnglish
Pages (from-to)158-167
Number of pages10
JournalJournal of Biomolecular Screening
Volume19
Issue number1
DOIs
StatePublished - Jan 2014

Keywords

  • cancer and cancer drugs
  • cell-based assays
  • kinases
  • phenotypic drug discovery

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biotechnology
  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery

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