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Ghelli Luserna Di Rora A , Beeharry N , Imbrogno E , Ferrari A , Robustelli V , Righi S , Sabattini E , Verga Falzacappa MV , Ronchini C , Testoni N , Baldazzi C , Papayannidis C , Abbenante MC , Marconi G , Paolini S , Parisi S , Sartor C , Fontana MC , De Matteis S , Iacobucci I , Pelicci PG , Cavo M , Yen TJ , Martinelli G
Targeting WEE1 to enhance conventional therapies for acute lymphoblastic leukemia
J Hematol Oncol. 2018 Aug 1;11(1) :99
PMID: 30068368    PMCID: PMC6090987   
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Abstract
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 inhibition of proliferation. CONCLUSIONS: Our data suggest that WEE1 plays a role in ALL blast's survival and is a bona fide target for therapeutic intervention. These data support the evaluation of the therapeutic potential of AZD-1775 as chemo-sensitizer agent for the treatment of B/T-ALL.
Notes
1756-8722 Ghelli Luserna Di Rora, Andrea Beeharry, Neil Imbrogno, Enrica Ferrari, Anna Robustelli, Valentina Righi, Simona Sabattini, Elena Verga Falzacappa, Maria Vittoria Ronchini, Chiara Testoni, Nicoletta Baldazzi, Carmen Papayannidis, Cristina Abbenante, Maria Chiara Marconi, Giovanni Paolini, Stefania Parisi, Sarah Sartor, Chiara Fontana, Maria Chiara De Matteis, Serena Iacobucci, Ilaria Pelicci, Pier Giuseppe Cavo, Michele Yen, Timothy J Martinelli, Giovanni CA191956/National Institutes of Health CA006927/National Institutes of Health DoD W81XWH-17-1-0136/U.S. Department of Defense 19226/Associazione Italiana per la Ricerca sul Cancro 306242-NGS-PTL/H2020 European Research Council Journal Article England J Hematol Oncol. 2018 Aug 1;11(1):99. doi: 10.1186/s13045-018-0641-1.