Combined inhibition of Chk1 and Wee1 as a new therapeutic strategy for mantle cell lymphoma

Rosaria Chilà, Alessandra Basana, Monica Lupi, Federica Guffanti, Eugenio Gaudio, Andrea Rinaldi, Luciano Cascione, Valentina Restelli, Chiara Tarantelli, Francesco Bertoni, Giovanna Damia, Laura Carrassa

Research output: Contribution to journalArticlepeer-review

Abstract

Mantle cell lymphoma (MCL) is an aggressive, incurable disease, characterized by a deregulated cell cycle. Chk1 and Wee1 are main regulators of cell cycle progression and recent data on solid tumors suggest that simultaneous inhibition of these proteins has a strong synergistic cytotoxic effect. The effects of a Chk1 inhibitor (PF-00477736) and a Wee1 inhibitor (MK-1775) have been herein investigated in a large panel of mature B-cell lymphoma cell lines. We found that MCL cells were the most sensitive to the Chk1 inhibitor PF-00477736 and Wee1 inhibitor MK-1775 as single agents. Possible involvement of the translocation t(11;14) in Chk1 inhibitor sensitivity was hypothesized. The combined inhibition of Chk1 and Wee1 was strongly synergistic in MCL cells, leading to deregulation of the cell cycle, with increased activity of CDK2 and CDK1, and activation of apoptosis. In vivo treatment with the drug combination of mice bearing JeKo-1 xenografts (MCL) had a marked antitumor effect with tumor regressions observed at non-toxic doses (best T/C%=0.54%). Gene expression profiling suggested effect on genes involved in apoptosis. The strong synergism observed by combining Chk1 and Wee1 inhibitors in preclinical models of MCL provides the rationale for testing this combination in the clinical setting.

Original languageEnglish
Pages (from-to)3394-3408
Number of pages15
JournalOncotarget
Volume6
Issue number5
Publication statusPublished - 2015

Keywords

  • cell cycle regulation
  • Chk1
  • mantle cell lymphoma
  • targeted therapy
  • Wee1

ASJC Scopus subject areas

  • Oncology

Fingerprint

Dive into the research topics of 'Combined inhibition of Chk1 and Wee1 as a new therapeutic strategy for mantle cell lymphoma'. Together they form a unique fingerprint.

Cite this