In vitro and in vivo single-agent efficacy of checkpoint kinase inhibition in acute lymphoblastic leukemia

Journal of Hematology & Oncology

Giovanni Martinelli⁵  Pier Giuseppe Pelicci²  Stefano Pileri⁵  Pier Luigi Zinzani⁵  Domenico Russo¹  Loredana Elia³  Antonella Vitale³  Maria Chiara Abbenante⁵  Emanuela Ottaviani⁵  Federica Cattina¹  Viviana Guadagnuolo⁵  Claudia Venturi⁵  Silvia Pomella⁵  Enrica Imbrogno⁵  Simona Righi⁵  Annalisa Lonetti⁴  Cristina Papayannidis⁵  Anna Ferrari⁵  Enrico Derenzini⁵  Claudio Agostinelli⁵  Maria Vittoria Verga Falzacappa²  Andrea Ghelli Luserna Di Rorà⁵  Ilaria Iacobucci⁵ 

[1] Hematology and BMT Unit, University of Brescia, Brescia, Italy;Department of Experimental Oncology, European Institute of Oncology, Milan, Italy;Division of Hematology, Department of Cellular Biotechnologies and Hematology, “Sapienza” University of Rome, Rome, Italy;Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy;Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology “L. e A. Seragnoli”, University of Bologna, Bologna, Italy

关键词: New targets;    Drug-sensitivity;    Checkpoint kinase;    DNA damage;    Acute lymphoblastic leukemia;   

Others  :  1233265
DOI  :  10.1186/s13045-015-0206-5

 received in 2015-07-09, accepted in 2015-09-28,  发布年份 2015

【 摘 要 】

Background

Although progress in children, in adults, ALL still carries a dismal outcome. Here, we explored the in vitro and in vivo activity of PF-00477736 (Pfizer), a potent, selective ATP-competitive small-molecule inhibitor of checkpoint kinase 1 (Chk1) and with lower efficacy of checkpoint kinase 2 (Chk2).

Methods

The effectiveness of PF-00477736 as single agent in B-/T-ALL was evaluated in vitro and in vivo studies as a single agent. 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. Finally, the action of PF-00477736 was assessed in vivo using leukemic mouse generated by a single administration of the tumorigenic agent N-ethyl-N-nitrosourea.

Results

Chk1 and Chk2 are overexpressed concomitant with the presence of genetic damage as suggested by the nuclear labeling for γ-H2A.X (Ser139) in 68 % of ALL patients. In human B- and T-ALL cell lines, inhibition of Chk1/2 as a single treatment strategy efficiently triggered the Chk1-Cdc25-Cdc2 pathway resulting in a dose- and time-dependent cytotoxicity, induction of apoptosis, and increased DNA damage. Moreover, treatment with PF-00477736 showed efficacy ex vivo in primary leukemic blasts separated from 14 adult ALL patients and in vivo in mice transplanted with T-ALL, arguing in favor of its future clinical evaluation in leukemia.

Conclusions

In vitro, ex vivo, and in vivo results support the inhibition of Chk1 as a new therapeutic strategy in acute lymphoblastic leukemia, and they provide a strong rationale for its future clinical investigation.

【 授权许可】

   
2015 Iacobucci et al.

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