Abstract 281P
Background
Acute myeloid leukemia (AML) is the most common acute type of leukemia in adults, with a disappointing prognosis and high death rate. Cytarabine (ara-C) is a primary first-line chemotherapy drug used in the treatment of AML, and resistance to it represents a major source of treatment failure. Sterile alpha motif and HD domain-containing protein 1 (SAMHD1), the only known human dNTPase, is known to attenuate ara-C cytotoxicity in AML cells, resulting in treatment failure and a poor prognosis. Therefore, selective inhibition of SAMHD1 in AML should prove a promising strategy for increasing the efficacy of ara-C. Nevertheless, no effective strategy to target SAMHD1 is available yet.
Methods
Cell culture, Monocyte isolation and differentiation, Cytotoxicity assays, Protein extraction and Western blot analysis, Immunoprecipitation, Immunofluorescent staining, Tissue staining, Mass spectrum system, mRNA analysis, RNA silencing, Flow cytometry, Orthotopic AML animal model, Heterotopic AML animal model.
Results
Here, we report that SAMHD1 is a novel HSP90-dependent protein in various tumor types. Pharmacological inhibition of HSP90 led to SAMHD1 depletion in a wide range of tumor cell types but had no or minimally effect on SAMHD1 of peripheral blood mononuclear cells (PBMCs) or macrophages from healthy donors due to the phosphorylation status on Thr 592. The combination of ara-C and HSP90 inhibitors showed a synergistic effect in killing AML cells. The HSP90 inhibitor also significantly enhanced the therapeutic efficacy of ara-C in both orthotopic and heterotopic models, alleviating tumor burden and prolonging survival.
Conclusions
Overall, these data suggest that the addition of an HSP90 inhibitor to ara-C-based chemotherapy represents a potential new treatment strategy for AML patients.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Xiaofang Yu.
Funding
National Natural Science Foundation of China (81772169).
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
107P - The efficacy of adjuvant chemotherapy according to the risk classification of recurrence based on the systemic inflammatory markers in patients with colorectal cancer liver metastases
Presenter: Masatsune Shibutani
Session: Poster display session
Resources:
Abstract
108P - Influence of liver metastasis locations on overall survival in patients with colorectal cancer
Presenter: Takayuki Sone
Session: Poster display session
Resources:
Abstract
109P - 18F-FDG PET/CT textural features as predictors of outcomes in patients with primary advanced colorectal cancer
Presenter: Jing Yang
Session: Poster display session
Resources:
Abstract
110P - D3 lymph node dissection may be necessary in clinical stage I right colon cancer
Presenter: Woong Bae Ji
Session: Poster display session
Resources:
Abstract
111P - Is preoperative chemoradiotherapy necessary for all patients with upper rectal cancer: One center retrospective study
Presenter: Jasur Madyarov
Session: Poster display session
Resources:
Abstract
112P - A retrospective analysis of the association between perioperative, post adjuvant carcinoembryonic antigen level and prognosis in stage III colorectal cancer
Presenter: Ryotaro Kozuki
Session: Poster display session
Resources:
Abstract
113P - Dicer contributes to chemoresistance in colorectal cancer via regulating a set of miRNAs and their downstream mRNAs
Presenter: Liang-Yi Hung
Session: Poster display session
Resources:
Abstract
114P - Efficacy and safety of the combination of bevacizumab with raltitrexed-based chemotherapy as second-line therapy in patients with metastatic colorectal cancer (mCRC): An interim analysis of a multicenter phase II trial
Presenter: Jun Zhu
Session: Poster display session
Resources:
Abstract
115P - Expression of Ki-67 as a prognostic factor in patients with colorectal cancer
Presenter: Kuantkan Zhabagin
Session: Poster display session
Resources:
Abstract
116P - Clinical significance and converionrate relevance of RAS genetic mutation analysis for unresectable colorectal liver metastases: A single-center retrospective study
Presenter: Meiling Ji
Session: Poster display session
Resources:
Abstract