دورية أكاديمية
Targeting WEE1 to enhance conventional therapies for acute lymphoblastic leukemia
| العنوان: | Targeting WEE1 to enhance conventional therapies for acute lymphoblastic leukemia |
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| المؤلفون: | Ghelli Luserna Di Rora A., Beeharry N., Imbrogno E., Ferrari A., Robustelli V., Righi S., Sabattini E., Verga Falzacappa M. V., Ronchini C., Testoni N., Baldazzi C., Papayannidis C., Abbenante M. C., Marconi G., Paolini S., Parisi S., Sartor C., Fontana M. C., De Matteis S., Iacobucci I., Pelicci P. G., Cavo M., Yen T. J., Martinelli G. |
| المساهمون: | Ghelli Luserna Di Rora, A., Beeharry, N., Imbrogno, E., Ferrari, A., Robustelli, V., Righi, S., Sabattini, E., Verga Falzacappa, M. V., Ronchini, C., Testoni, N., Baldazzi, C., Papayannidis, C., Abbenante, M. C., Marconi, G., Paolini, S., Parisi, S., Sartor, C., Fontana, M. C., De Matteis, S., Iacobucci, I., Pelicci, P. G., Cavo, M., Yen, T. J., Martinelli, G. |
| سنة النشر: | 2018 |
| المجموعة: | Università degli Studi di Cagliari: UNICA IRIS |
| مصطلحات موضوعية: | Acute lymphoblastic leukemia, Chemo-sensitizer agent, G2/M checkpoint, WEE1 inhibitor |
| الوصف: | Background: Despite the recent progress that has been made in the understanding and treatment of acute lymphoblastic leukemia (ALL), the outcome is still dismal in adult ALL cases. Several studies in solid tumors identified high expression of WEE1 kinase as a poor prognostic factor and reported its role as a cancer-conserving oncogene that protects cancer cells from DNA damage. Therefore, the targeted inhibition of WEE1 kinase has emerged as a rational strategy to sensitize cancer cells to antineoplastic compounds, which we evaluate in this study. Methods: The effectiveness of the selective WEE1 inhibitor AZD-1775 as a single agent and in combination with different antineoplastic agents in B and T cell precursor ALL (B/T-ALL) was evaluated in vitro and ex vivo studies. The efficacy of the compound in terms of cytotoxicity, induction of apoptosis, and changes in gene and protein expression was assessed using different B/T-ALL cell lines and confirmed in primary ALL blasts. Results: We showed that WEE1 was highly expressed in adult primary ALL bone marrow and peripheral blood blasts (n = 58) compared to normal mononuclear cells isolated from the peripheral blood of healthy donors (p = 0.004). Thus, we hypothesized that WEE1 could be a rational target in ALL, and its inhibition could enhance the cytotoxicity of conventional therapies used for ALL. We evaluated the efficacy of AZD-1775 as a single agent and in combination with several antineoplastic agents, and we elucidated its mechanisms of action. AZD-1775 reduced cell viability in B/T-ALL cell lines by disrupting the G2/M checkpoint and inducing apoptosis. These findings were confirmed in human primary ALL bone marrow and peripheral blood blasts (n = 15). In both cell lines and primary leukemic cells, AZD-1775 significantly enhanced the efficacy of several tyrosine kinase inhibitors (TKIs) such as bosutinib, imatinib, and ponatinib, and of chemotherapeutic agents (clofarabine and doxorubicin) in terms of the reduction of cell viability, apoptosis induction, and ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | info:eu-repo/semantics/altIdentifier/pmid/30068368; info:eu-repo/semantics/altIdentifier/wos/WOS:000440541400001; volume:11; issue:1; numberofpages:18; journal:JOURNAL OF HEMATOLOGY & ONCOLOGY; http://hdl.handle.net/11584/284348Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85051075414; https/jhoonline.biomedcentral.com/articles/10.1186/s13045-018-0641-1 |
| DOI: | 10.1186/s13045-018-0641-1 |
| الإتاحة: | https://doi.org/10.1186/s13045-018-0641-1Test http://hdl.handle.net/11584/284348Test |
| حقوق: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.56E07154 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1186/s13045-018-0641-1 |
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