Inhibition of maternal embryonic leucine zipper kinase with OTSSP167 displays potent anti-leukemic effects in chronic lymphocytic leukemia

Abstract

TP53 pathway defects contributed to therapy resistance and adverse clinical outcome in chronic lymphocytic leukemia (CLL), which represents an unmet clinical need with few therapeutic options. Maternal embryonic leucine zipper kinase (MELK) is a novel oncogene, which plays crucial roles in mitotic progression and stem cell maintenance. OTSSP167, an orally administrated inhibitor targeting MELK, is currently in a phase I/II clinical trial in patients with advanced breast cancer and acute myeloid leukemia. Yet, no investigation has been elucidated to date regarding the oncogenic role of MELK and effects of OTSSP167 in chronic lymphocytic leukemia (CLL). Previous studies confirmed MELK inhibition abrogated cancer cell survival via p53 signaling pathway. Thus, we aimed to determine the biological function of MELK and therapeutic potential of OTSSP167 in CLL. Herein, MELK over-expression was observed in CLL cells, and correlated with higher WBC count, advanced stage, elevated LDH, increased β2-MG level, unmutated IGHV, positive ZAP-70, deletion of 17p13 and inferior prognosis of CLL patients. In accordance with functional enrichment analyses in gene expression profiling, CLL cells with depletion or inhibition of MELK exhibited impaired cell proliferation, enhanced fast-onset apoptosis, induced G2/M arrest, attenuated cell chemotaxis and promoted sensitivity to fludarabine and ibrutinib. However, gain-of-function assay showed increased cell proliferation and cell chemotaxis. In addition, OTSSP167 treatment reduced phosphorylation of AKT and ERK1/2. It decreased FoxM1 phosphorylation, expression of FoxM1, cyclin B1 and CDK1, while up-regulating p53 and p21 expression. Taken together, MELK served as a candidate of therapeutic target in CLL. OTSSP167 exhibits potent anti-tumor activities in CLL cells, highlighting a novel molecule-based strategy for leukemic interventions.

Inhibition of MELK produces potential anti‐tumour effects in bladder cancer by inducing G1/S cell cycle arrest via the ATM/CHK2/p53 pathway

“…In contrast, MELK silencing was found to contribute to the delay of S phase progression by Beke et al andKig et al 13,30 Our study revealed that MELK may act as a negative regulator of the G1/S transition, which was consistent with Beke et al andKig et al To investigate the reason that MELK plays a different role in cell cycle progression according to previous studies, cell cycle assays of other cancer cell lines, such as liver cancer and kidney cancer, were assessed following MELK being knocked down. Moreover, MELK has been shown in some studies to promote tumorigenesis via the p53 pathway 13,23,25,[30][31][32]. Owing to the lack of additional tumour cell lines, we could not conclude that p53 affects the role of MELK in the cell cycle.…”

“…[6][7][8] MELK was associated with mitotic progression and DNA damage. 23 High levels of MELK are correlated with clinically aggressive disease and poor survival. 23 High levels of MELK are correlated with clinically aggressive disease and poor survival.…”

“…23 High levels of MELK are correlated with clinically aggressive disease and poor survival. 19,[22][23][24][25] A number of studies have shown that MELK inhibition also increases sensitivity to radiation and chemotherapy in pre-clinical adult cancer models, suggesting that combination treatments may also be effective strategies. 19,[22][23][24][25] A number of studies have shown that MELK inhibition also increases sensitivity to radiation and chemotherapy in pre-clinical adult cancer models, suggesting that combination treatments may also be effective strategies.…”

“…15,23,24 Further, genomic or pharmacologic inhibition of MELK has been shown to suppress tumour growth in vitro and in pre-clinical adult cancer models, indicating that this kinase is a potential therapeutic target. 23,[26][27][28][29] Although the mechanisms by which MELK mediates aggressive tumour growth are not completely understood, MELK inhibition has been confirmed to lead to the consecutive phosphorylation of ataxia telangiectasia-mutated (ATM) and cell cycle checkpoint kinase 2 (CHK2) and to the up-regulation of p53 and p21. 23,[26][27][28][29] Although the mechanisms by which MELK mediates aggressive tumour growth are not completely understood, MELK inhibition has been confirmed to lead to the consecutive phosphorylation of ataxia telangiectasia-mutated (ATM) and cell cycle checkpoint kinase 2 (CHK2) and to the up-regulation of p53 and p21.…”

“…23 Several phase I/ II clinical trials in patients with advanced breast cancer and acute myeloid leukaemia have been launched to test the therapeutic potential of OTSSP167. Interestingly, MELK was implicated in tumorigenesis via the p53 pathway, 13,23,25,[30][31][32] which suggested the potential utility of OTSSP167 in treating relapsed/refractory BCa. Interestingly, MELK was implicated in tumorigenesis via the p53 pathway, 13,23,25,[30][31][32] which suggested the potential utility of OTSSP167 in treating relapsed/refractory BCa.…”