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.
Highlights
Mantle cell lymphoma (MCL) is one of the most common lymphoma subtypes, accounting for 5–10% of all non-Hodgkin’s lymphomas [1], and its prognosis is the worst among B-cell lymphomas [2, 3]
MCL cell lines display a high sensitivity to Chk1 and Wee1 inhibitors as single agents
We investigated the effects of Chk1 and Wee1 inhibition in a large panel of lymphoma cell lines: 35 mature B-cell lymphoma cell lines comprising ten MCL and 25 DLBCL cell lines, by treating them with specific Chk1 and Wee1 inhibitors, respectively PF-00477736 and MK1775
Summary
Mantle cell lymphoma (MCL) is one of the most common lymphoma subtypes, accounting for 5–10% of all non-Hodgkin’s lymphomas [1], and its prognosis is the worst among B-cell lymphomas [2, 3]. Deregulation of cell cycle is the characteristic pathogenic hallmark of MCL. The disease is characterized by frequent additional genetic lesions deregulating genes, such as CDKN2A, CDK4, TP53 and ATM, involved in cell cycle regulation and DNA damage response [7, 8]. In normal cells genomic stability and integrity is assured by the existence of surveillance pathways that control key processes such as DNA repair, cell cycle checkpoints, apoptosis and transcription [9, 10]. The checkpoint kinases Chk and Wee are key regulators of DNA damage www.impactjournals.com/oncotarget surveillance pathways [11,12,13]. Wee has a major cell cycle function in control of the G2/M transition and in ensuring faithful DNA replication [11, 12, 16]. Little is known about the putative role and effects of Chk and Wee inhibitors in lymphomas
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