Abstract
Treatment options for TP53-mutated lymphoid tumors are very limited. In experimental models, TP53-mutated lymphomas were sensitive to direct inhibition of checkpoint kinase 1 (Chk1), a pivotal regulator of replication. We initially tested the potential of the highly specific Chk1 inhibitor SCH900776 to synergize with nucleoside analogs (NAs) fludarabine, cytarabine and gemcitabine in cell lines derived from B-cell malignancies. In p53-proficient NALM-6 cells, SCH900776 added to NAs enhanced signaling towards Chk1 (pSer317/pSer345), effectively blocked Chk1 activation (Ser296 autophosphorylation), increased replication stress (p53 and γ-H2AX accumulation) and temporarily potentiated apoptosis. In p53-defective MEC-1 cell line representing adverse chronic lymphocytic leukemia (CLL), Chk1 inhibition together with NAs led to enhanced and sustained replication stress and significantly potentiated apoptosis. Altogether, among 17 tested cell lines SCH900776 sensitized four of them to all three NAs. Focusing further on MEC-1 and co-treatment of SCH900776 with fludarabine, we disclosed chromosome pulverization in cells undergoing aberrant mitoses. SCH900776 also increased the effect of fludarabine in a proportion of primary CLL samples treated with pro-proliferative stimuli, including those with TP53 disruption. Finally, we observed a fludarabine potentiation by SCH900776 in a T-cell leukemia 1 (TCL1)-driven mouse model of CLL. Collectively, we have substantiated the significant potential of Chk1 inhibition in B-lymphoid cells.
Highlights
B-cell malignancies represent a heterogeneous group of lymphoproliferative diseases involving both rapidly growing and more indolent leukemia and lymphomas. mutations in the tumor-suppressor TP53 are comparatively less frequent than in solid tumors, they are uniformly associated with an unfavorable outcome in respective patients [1]
The p53 protein integrates signals related to DNA damage, including the signaling mediated by checkpoint kinase 1 (Chk1), and decides a cells fate, principally between cell cycle arrest with DNA repair and apoptosis [8]
In order to gain insight on SCH900776 interference in DNA damage response (DDR), we first analyzed its impact on Chk1 protein using NALM-6 cell line with wt-p53 status and baseline Chk1 autophosphorylation on Ser-296
Summary
B-cell malignancies represent a heterogeneous group of lymphoproliferative diseases involving both rapidly growing and more indolent leukemia and lymphomas. mutations in the tumor-suppressor TP53 are comparatively less frequent than in solid tumors, they are uniformly associated with an unfavorable outcome in respective patients [1]. The inhibition of ataxiatelangiectasia mutated and Rad-3 related (ATR) kinase operating in the DNA damage response (DDR) pathway has been identified as a potential alternative therapeutic strategy in CLL [4]. ATR is a key molecule activating the DDR pathway through phosphorylation of checkpoint kinase 1 (Chk1) upon recognition of DNA damage [5, 6]. Chk represents a master cell cycle regulator which primarily supervises replication through intra-S and G2/M checkpoints and is involved in other control points in G1 phase and mitosis [7]. The p53 protein integrates signals related to DNA damage, including the signaling mediated by Chk, and decides a cells fate, principally between cell cycle arrest with DNA repair and apoptosis [8]. Some studies convincingly demonstrated a synergy between p53 deficiency and Chk inhibition [10, 11], but other more comprehensive approaches indicated that p53 status is only one of the decisive factors [12, 13]
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