Inhibition of the spindle assembly checkpoint kinase Mps-1 as a novel therapeutic strategy in malignant mesothelioma

Abstract

Malignant mesothelioma (MM) is an aggressive malignancy, highly resistant to current medical and surgical therapies, whose tumor cells characteristically show a high level of aneuploidy and genomic instability. We tested our hypothesis that targeting chromosomal instability in MM would improve response to therapy.TTK/Mps-1 (monopolar spindle 1 kinase) is a kinase of the spindle assembly checkpoint that controls cell division and cell fate. CFI-402257 is a novel, selective inhibitor of Mps-1 with antineoplastic activity. We found that CFI-402257 suppresses MM growth. We found that Mps-1 is overexpressed in MM and that its expression correlates with poor patients’ outcome. In vitro, CFI-402257-mediated inhibition of Mps-1 resulted in abrogation of the mitotic checkpoint, premature progression through mitosis, marked aneuploidy and mitotic catastrophe. In vivo, CFI-402257 reduced MM growth in an orthotopic, syngeneic model, when used as a single agent, and more so when used in combination with cisplatin+pemetrexed, the current standard of care.Our preclinical findings indicate that CFI-402257 is a promising novel therapeutic agent to improve the efficacy of the current chemotherapeutic regimens for MM patients.

Expression of cancer–testis antigens in esophageal cancer and their progress in immunotherapy

“…It can phosphorylate serine, threonine, and tyrosine hydroxyamino acids, and is associated with cell proliferation (Tao et al 2012 ) and cell invasion (King et al 2018 ). It is also a critical regulator of the spindle assembly checkpoint (SAC), which functions to maintain genomic integrity (Thu et al 2018 ) and controls cell fate (Szymiczek et al 2017 ). TTK is expressed at relatively high levels in testis, thymus tissues and various malignant tumor tissues (Kaistha et al 2014 ; Miao et al 2016 ; Choi et al 2017 ; Szymiczek et al 2017 ; Chen et al 2018 ; King et al 2018 ), but is not detected in most other benign tissues (Mills et al 1992 ).…”

“…He et al ( 2018 ) indicate that this gene is vital in the progression of ESCC, but also decide the prognosis of patients. In other cancer types, the overexpression of the Mps1-encoding TTK gene was correlated with poor patients’ outcome of HCC (Choi et al 2017 ), malignant mesothelioma (Szymiczek et al 2017 ) and so on.…”

“…TTK used in the clinical study is considered to be very appropriate because it was expressed in the great majority (> 95%) of esophageal cancers, was expressed specifically in cancer cells and testis (cancer–testis antigens), was shown to be essential for the survival of cancer cells (Mizukami et al 2008 ), and most importantly revealed very strong immunogenicity (Suda et al 2007 ; Kono et al 2009 , 2012 ). Besides, it is also a vital regulator of the spindle assembly checkpoint (SAC), which functions to maintain genomic integrity (Thu et al 2018 ) and controls cell fate (Szymiczek et al 2017 ). These evidences strongly encouraged researchers to apply this CTA peptide as a candidate target for anti-cancer therapy.…”

“…TTK, a genome-surveillance mechanism that is important for cell survival, and has emerged as a candidate target for anticancer therapy (Mason et al 2017 ). Inhibition of TTK has emerged as a promising therapeutic strategy for the treatment of aneuploid tumors, with triple-negative breast cancer (TNBC) (Maia et al 2015 ; Riggs et al 2017 ; Thu et al 2018 ; Zhu et al 2018 ) and malignant mesothelioma (Szymiczek et al 2017 ) important focus of clinical development. Human cancer cells treated with Mps1 inhibitor exhibit effects consistent with Mps1 kinase inhibition, specifically spindle assembly checkpoint inactivation, leading to chromosome missegregation, aneuploidy, and ultimately cell death (Mason et al 2017 ).…”

Identification and validation of aberrant regulation of miR-445-3p /TTK , miR-140-5p/TTK and miR-133b/CDCA8 in small-cell lung cancer via bioinformatics analysis

“…Du et al believed that TTK could play a tumorigenic role in neuroendocrine lung cancer in combination with LMO1 [28]. Furthermore, TTK inhibitors have been used in antitumor therapy [29][30][31]. Zheng et al showed that TTK inhibitors induced pronounced anticancer effects by augmenting polyploidy and apoptosis in NSCLC [32].…”