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Author Notes:

Corresponding Author: Christopher C. Porter, 1760 Haygood Drive E370 Health Sciences Research Building Atlanta, GA 30322, Phone: 404-727-4881, Fax: 404-727-4455, chris.porter@emory.edu.

Subjects:

Research Funding:

This work was supported by grants from the National Institutes of Health to C.C. Porter (CA172385), the University of Colorado Cancer Center (CA046934) to C.C. Porter, and the CU Medical Scientist Training Program (GM008497) to T.B. Garcia.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Oncology
  • ACUTE MYELOID-LEUKEMIA
  • ACUTE LYMPHOBLASTIC-LEUKEMIA
  • ADVANCED SOLID TUMORS
  • PARP INHIBITORS
  • PHASE-I
  • POLY(ADP-RIBOSE) POLYMERASE
  • THERAPEUTIC APPROACH
  • REPAIR DEFECTS
  • OVARIAN-CANCER
  • CELLS

A Small-Molecule Inhibitor of WEE1, AZD1775, Synergizes with Olaparib by Impairing Homologous Recombination and Enhancing DNA Damage and Apoptosis in Acute Leukemia

Journal Title:

Molecular Cancer Therapeutics

Volume:

Volume 16, Number 10

Publisher:

, Pages 2058-2068

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Although some patients with acute leukemia have good prognoses, the prognosis of adult and pediatric patients who relapse or cannot tolerate standard chemotherapy is poor. Inhibition of WEE1 with AZD1775 has been shown to sensitize cancer cells to genotoxic chemotherapies, including cytarabine in acute myeloid leukemia (AML) and T-ALL. Inhibition of WEE1 impairs homologous recombination by indirectly inhibiting BRCA2. Thus, we sought to determine whether AZD1775 could sensitize cells to the PARP1/2 inhibitor olaparib. We found that combined treatment with AZD1775 and olaparib was synergistic in AML and ALL cells, and this combination impaired proliferative capacity upon drug withdrawal. AZD1775 impaired homologous recombination in olaparib-treated cells, resulting in enhanced DNA damage accumulation and apoptosis induction. This combination enhanced disease control and increased survival in a murine AML model. Furthermore, we demonstrated that combined treatment with AZD1775 and olaparib reduces proliferation and colony formation and increases apoptosis in AML patient samples. In aggregate, these studies raise the possibility of rational combinations of targeted agents for leukemia in patients for whom conventional chemotherapeutics may not be effective or well tolerated.

Copyright information:

©2017 AACR.

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