Effects of the Selective MPS1 Inhibitor MPS1-IN-3 on Glioblastoma Sensitivity to Antimitotic Drugs

Tannous, Bakhos A.; Kerami, Mariam; Stoop, Petra M. van der; Kwiatkowski, Nicholas; Wang, Jinhua; Zhou, Wenjun; Keßler, Almuth F.; Lewandrowski, Grant K.; Hiddingh, Lotte; Sol, Nik; Lagerweij, Tonny; Wedekind, Laurine E.; Niers, Johanna M.; Barazas, Marco; Nilsson, R. Jonas A.; Geerts, Dirk; Hamer, Philip C. De Witt; Hagemann, Carsten; Vandertop, W. Peter; Tellingen, Olaf van; Noske, David P.; Gray, Nathanael S.; Würdinger, Thomas

doi:10.1093/jnci/djt168

Cited by 106 publications

(121 citation statements)

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“…Extremely shortened mitosis induces massive chromosome missegregation and/or tetraploidization that elevates cell stress beyond the lethal level [164,165]. In line with the idea, inhibitors of Mps1 kinase were shown to exert anti-tumor activities [166][167][168], and anti-SAC compounds were reported to sensitize cancer cells to microtubule-targeting drugs [169][170][171][172].…”

Section: Accepted Manuscriptmentioning

confidence: 98%

Chromosomal instability: A common feature and a therapeutic target of cancer

Tanaka

Hirota

2016

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Section: Accepted Manuscriptmentioning

confidence: 98%

Chromosomal instability: A common feature and a therapeutic target of cancer

Tanaka

Hirota

2016

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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“…Mps1-IN-3 50 nM (Tannous et al, 2013) SAC bypass (Tannous et al, 2013) Glioma (Tannous et al, 2013) NMS-P715 8 nM (Colombo et al, 2010) Failure in recruitment of Mad1, Mad2, Bub1 and Bub3 (Colombo et al, 2010) Melanoma (Colombo et al, 2010) SAC bypass (Slee et al, 2014) Short mitotic duration (Colombo et al, 2010;Gurden et al, 2015) Apoptosis (Colombo et al, 2010;Slee et al, 2014;Maachani et al, 2015).…”

Section: Chromosome Misalignment and Missegregationmentioning

confidence: 99%

“…A high expression of Mps1 is associated with poor survival of patients with glioma and pancreatic cancer (Tannous et al, 2013;Slee et al, 2014;Maachani et al, 2015), although it is associated with better survival in those with triple-negative breast cancer (Maire et al, 2013). In addition, the Mps1-encoding TTK gene is highly mutated in colorectal cancer with microsatellite instability (Niittymaki et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

TC Mps1 12, a novel Mps1 inhibitor, suppresses the growth of hepatocellular carcinoma cells via the accumulation of chromosomal instability

Choi

Min

Pyo

et al. 2017

British J Pharmacology

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contributed equally to the work. BACKGROUND AND PURPOSEChromosomal instability is not only a hallmark of cancer but also an attractive therapeutic target. A diverse set of mitotic kinases maintains chromosomal stability. One of these is monopolar spindle 1 (Mps1, also known as TTK), which is essential for chromosome alignment and for the spindle assembly checkpoint (SAC). Pharmacological inhibition of Mps1 has been suggested as a cancer therapeutic; however, despite the existence of a novel Mps1 inhibitor, TC Mps1 12, no such studies have been performed. EXPERIMENTAL APPROACHThe effects of TC Mps1 12 on cell viability, chromosome alignment, centrosome number, mitotic duration, apoptosis and SAC were determined in hepatocellular carcinoma (HCC) cells. In addition, the association of Mps1 expression with the overall survival of HCC patients was analysed. KEY RESULTSTreatment of human HCC cells with TC Mps1 12 led to chromosome misalignment and missegregation, and disorganization of centrosomes. Even in the presence of these errors, TC Mps1 12-treated cells overrode the SAC, resulting in a shortened mitotic duration and mitotic slippage. This mitotic catastrophe triggered apoptosis and, finally, inhibited the growth of HCC cells. In addition, the expression of the Mps1-encoding TTK gene was associated with poor overall survival of HCC patients. CONCLUSION AND IMPLICATIONSTC Mps1 12 results in the accumulation of chromosomal instabilities and mitotic catastrophe in HCC cells. Overall, these data demonstrate that the inhibition of Mps1 kinase using TC Mps1 12 is a promising therapeutic approach for liver cancer.Abbreviations HCC, hepatocellular carcinoma; MCC, mitotic checkpoint complex; Mps1 (TTK), monopolar spindle 1; SAC, spindle assembly checkpoint

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“…MPS1 has been suggested to be dysregulated in cancer cells; specifically, MPS1 mRNA expression is elevated in a number of cancers relative to normal tissue, including thyroid, breast, lung, bladder, and glioblastoma, higher levels correlating with a higher histologic grade, aggressiveness, and poor patient survival in breast cancer, glioblastoma, and pancreatic ductal adenocarcinoma (11)(12)(13)(14)(15)(16)(17). Furthermore, breast cancer cell lines deficient in the tumor-suppressor protein PTEN have been reported to be more sensitive to MPS1 depletion or kinase inhibition (18).…”

Section: Introductionmentioning

confidence: 99%

Naturally Occurring Mutations in the MPS1 Gene Predispose Cells to Kinase Inhibitor Drug Resistance

et al. 2015

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Acquired resistance to therapy is perhaps the greatest challenge to effective clinical management of cancer. With several inhibitors of the mitotic checkpoint kinase MPS1 in preclinical development, we sought to investigate how resistance against these inhibitors may arise so that mitigation or bypass strategies could be addressed as early as possible. Toward this end, we modeled acquired resistance to the MPS1 inhibitors AZ3146, NMS-P715, and CCT251455, identifying five point mutations in the kinase domain of MPS1 that confer resistance against multiple inhibitors. Structural studies showed how the MPS1 mutants conferred resistance by causing steric hindrance to inhibitor binding. Notably, we show that these mutations occur in nontreated cancer cell lines and primary tumor specimens, and that they also preexist in normal lymphoblast and breast tissues. In a parallel piece of work, we also show that the EGFR p.T790M mutation, the most common mutation conferring resistance to the EGFR inhibitor gefitinib, also preexists in cancer cells and normal tissue. Our results therefore suggest that mutations conferring resistance to targeted therapy occur naturally in normal and malignant cells and these mutations do not arise as a result of the increased mutagenic plasticity of cancer cells. Cancer Res; 75(16); 3340-54. Ó2015 AACR.

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Effects of the Selective MPS1 Inhibitor MPS1-IN-3 on Glioblastoma Sensitivity to Antimitotic Drugs

Abstract: Our results collectively demonstrate that MPS1, a putative therapeutic target in glioblastoma, can be selectively inhibited by MPS1-IN-3 sensitizing glioblastoma cells to antimitotic drugs.

Cited by 106 publications

References 40 publications

Chromosomal instability: A common feature and a therapeutic target of cancer

Chromosomal instability: A common feature and a therapeutic target of cancer

TC Mps1 12, a novel Mps1 inhibitor, suppresses the growth of hepatocellular carcinoma cells via the accumulation of chromosomal instability

Naturally Occurring Mutations in the MPS1 Gene Predispose Cells to Kinase Inhibitor Drug Resistance

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