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posted on 2023-04-03, 15:44 authored by Tamara B. Garcia, Jonathan C. Snedeker, Dmitry Baturin, Lori Gardner, Susan P. Fosmire, Chengjing Zhou, Craig T. Jordan, Sujatha Venkataraman, Rajeev Vibhakar, Christopher C. Porter Inhibition of endogenous P53 in OCI-AML3 cells does not enhance the combinatorial activity of AZD1775 and olaparib. A-C. OCI-AML3 parental (A), MiG (B), and MiG-DDp53 (C) cells were treated with DMSO (vehicle control), olaparib (2 uM), and/or AZD1775 (200 nM) for 72 hr. Viable cell counts are normalized to cells receiving no treatment (NT). Results are shown as mean {plus minus} SEM from three independent experiments. *, P < 0.05. **, P < 0.01. ***, P < 0.001.
Funding
NIH
University of Colorado Cancer Center
CU Medical Scientist Training Program
History
ARTICLE 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. Mol Cancer Ther; 16(10); 2058–68. ©2017 AACR.
