Combined inhibition of Chk1 and Wee1 as a new therapeutic strategy for mantle cell lymphoma
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Rosaria Chilà1, Alessandra Basana1, Monica Lupi1, Federica Guffanti1, Eugenio Gaudio2, Andrea Rinaldi2, Luciano Cascione2,3, Valentina Restelli1, Chiara Tarantelli2, Francesco Bertoni2,3, Giovanna Damia1, Laura Carrassa1
1Laboratory of Molecular Pharmacology and Laboratory of Cancer Pharmacology, Department of Oncology, IRCCS- Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy
2Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland
3Lymphoma Unit, IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
Laura Carrassa, e-mail: [email protected]
Giovanna Damia, e-mail: [email protected]
Francesco Bertoni, e-mail: [email protected]
Keywords: Chk1, Wee1, targeted therapy, mantle cell lymphoma, cell cycle regulation
Received: August 04, 2014 Accepted: October 09, 2014 Published: October 25, 2014
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.
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