Targeting WEE1 to enhance conventional therapies for acute lymphoblastic leukemia

Andrea Ghelli Luserna Di Rorà, Neil Beeharry, Enrica Imbrogno, Anna Ferrari, Valentina Robustelli, Simona Righi, Elena Sabattini, Maria Vittoria Verga Falzacappa, Chiara Ronchini, Nicoletta Testoni, Carmen Baldazzi, Cristina Papayannidis, Maria Chiara Abbenante, Giovanni Marconi, Stefania Paolini, Sarah Parisi, Chiara Sartor, Maria Chiara Fontana, Serena De Matteis, Ilaria IacobucciPier Giuseppe Pelicci, Michele Cavo, Timothy J Yen, Giovanni Martinelli

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)99
JournalJournal of Hematology and Oncology
Volume11
Issue number1
DOIs
Publication statusPublished - Aug 1 2018

Fingerprint

Precursor Cell Lymphoblastic Leukemia-Lymphoma
Therapeutics
Antineoplastic Agents
Apoptosis
Cell Line
Neoplasms
Cell Survival
Phosphotransferases
Biphenotypic Acute Leukemia
Bone Marrow
T-Lymphoid Precursor Cells
Blood Donors
Oncogenes
Protein-Tyrosine Kinases
Doxorubicin
DNA Damage
Gene Expression

Cite this

Targeting WEE1 to enhance conventional therapies for acute lymphoblastic leukemia. / Ghelli Luserna Di Rorà, 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.

In: Journal of Hematology and Oncology, Vol. 11, No. 1, 01.08.2018, p. 99.

Research output: Contribution to journalArticle

Ghelli Luserna Di Rorà, 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 2018, 'Targeting WEE1 to enhance conventional therapies for acute lymphoblastic leukemia', Journal of Hematology and Oncology, vol. 11, no. 1, pp. 99. https://doi.org/10.1186/s13045-018-0641-1
Ghelli Luserna Di Rorà, 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. / Targeting WEE1 to enhance conventional therapies for acute lymphoblastic leukemia. In: Journal of Hematology and Oncology. 2018 ; Vol. 11, No. 1. pp. 99.
@article{0499b08f719d486e9fa5813edf10a84f,
title = "Targeting WEE1 to enhance conventional therapies for acute lymphoblastic leukemia",
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.",
author = "{Ghelli Luserna Di Ror{\`a}}, Andrea and Neil Beeharry and Enrica Imbrogno and Anna Ferrari and Valentina Robustelli and Simona Righi and Elena Sabattini and {Verga Falzacappa}, {Maria Vittoria} and Chiara Ronchini and Nicoletta Testoni and Carmen Baldazzi and Cristina Papayannidis and Abbenante, {Maria Chiara} and Giovanni Marconi and Stefania Paolini and Sarah Parisi and Chiara Sartor and Fontana, {Maria Chiara} and {De Matteis}, Serena and Ilaria Iacobucci and Pelicci, {Pier Giuseppe} and Michele Cavo and Yen, {Timothy J} and Giovanni Martinelli",
year = "2018",
month = "8",
day = "1",
doi = "10.1186/s13045-018-0641-1",
language = "English",
volume = "11",
pages = "99",
journal = "Journal of Hematology and Oncology",
issn = "1756-8722",
publisher = "BioMed Central Ltd.",
number = "1",

}

TY - JOUR

T1 - Targeting WEE1 to enhance conventional therapies for acute lymphoblastic leukemia

AU - Ghelli Luserna Di Rorà, Andrea

AU - Beeharry, Neil

AU - Imbrogno, Enrica

AU - Ferrari, Anna

AU - Robustelli, Valentina

AU - Righi, Simona

AU - Sabattini, Elena

AU - Verga Falzacappa, Maria Vittoria

AU - Ronchini, Chiara

AU - Testoni, Nicoletta

AU - Baldazzi, Carmen

AU - Papayannidis, Cristina

AU - Abbenante, Maria Chiara

AU - Marconi, Giovanni

AU - Paolini, Stefania

AU - Parisi, Sarah

AU - Sartor, Chiara

AU - Fontana, Maria Chiara

AU - De Matteis, Serena

AU - Iacobucci, Ilaria

AU - Pelicci, Pier Giuseppe

AU - Cavo, Michele

AU - Yen, Timothy J

AU - Martinelli, Giovanni

PY - 2018/8/1

Y1 - 2018/8/1

N2 - 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.

AB - 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.

U2 - 10.1186/s13045-018-0641-1

DO - 10.1186/s13045-018-0641-1

M3 - Article

C2 - 30068368

VL - 11

SP - 99

JO - Journal of Hematology and Oncology

JF - Journal of Hematology and Oncology

SN - 1756-8722

IS - 1

ER -