Targeting WEE1 to enhance conventional therapies for acute lymphoblastic leukemia

Abstract

BackgroundDespite 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.MethodsThe 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.ResultsWe 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (10.1186/s13045-018-0641-1) contains supplementary material, which is available to authorized users.

A WEE1 family business: regulation of mitosis, cancer progression, and therapeutic target

“…Few studies have analyzed WEE1 and PKMYT1 expression in hematological malignancies. Our group showed that WEE1 kinase is highly expressed in acute lymphoblastic leukemia (ALL) cell lines and primary cells in comparison with normal hematopoietic cells, and that PKMYT1 is upregulated in relapsed ALL samples compared with nonmalignant hematopoietic cells [ 35 ]. Moreover, we demonstrated that ALL cells are dependent on WEE1 functionality for their survival and proliferation and that PKMYT1 levels may influence the sensitivity to the WEE1 inhibitor AZD-1775 [ 35 ].…”

“…Our group showed that WEE1 kinase is highly expressed in acute lymphoblastic leukemia (ALL) cell lines and primary cells in comparison with normal hematopoietic cells, and that PKMYT1 is upregulated in relapsed ALL samples compared with nonmalignant hematopoietic cells [ 35 ]. Moreover, we demonstrated that ALL cells are dependent on WEE1 functionality for their survival and proliferation and that PKMYT1 levels may influence the sensitivity to the WEE1 inhibitor AZD-1775 [ 35 ]. Similar results on the role of WEE1 were obtained in multiple myeloma (MM), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and chronic lymphocyte leukemia (CLL) [ 36 – 39 ].…”

“… [ 35 – 40 , 43 , 54 ] Copy number Gain AML Biological effect or prognostic value unknown [ 55 ] PKMYT1 Over-expression ALL; MM Crucial for cell viability of cancer cells (experimentally proven). [ 35 , 44 ] Solid tumors WEE1 Over-expression GC; MaM; GL; OC; CC Associated with lymph node involvement, induction of metastasis, increased biomarkers of proliferation (CCND1, Ki67 or CCNA1), resistance to treatment and poor overall survival. [ 48 – 51 , 56 – 60 ] Mutation PA Insertion causing decrease WEE1 expression upon DNA damage [ 33 ] PKMYT1 Over-expression HC; CC; GLB; NSCLC; N; GS Associated with tumor progression, aggressive disease and poor overall survival.…”

“…The sensitivity to WEE1 kinase inhibitors in relation to TP53 mutational status remains controversial. Indeed, some studies reported increased sensitivity of TP53 mutant cell lines to WEE1 inhibitors in comparison to TP53 wild-type ones [ 62 , 63 ], while others showed no association between p53 functionality and the effectiveness of WEE1 inhibition [ 35 , 64 ]. These discrepancies may be linked to the intrinsic chromosomal instability of the analyzed tumors and to additional alterations deregulating the G1 checkpoint in TP53 wild-type cases that may enhance the sensitivity to WEE1 targeting.…”

Cancer Management by Tyrosine Kinase Inhibitors: Efficacy, Limitation, and Future Strategies

“…[165]. For acute lymphocytic lymphoma, a WEE1 inhibitor AZD-1775 is proven to significantly enhance the efficacy of several tyrosine kinase inhibitors, such as imatinib, bosutinib, and ponatinib [168], or similarly, vitamin K1 with sorafenib in treating HCC [151] and antiestrogen fulvestrant with vandetanib in NSCLC.…”