Oss, March, 16th, 2017 – In a research article which appeared online today in Oncotarget, NTRC scientists, in collaboration with Prof. Dr. René Medema from the Netherlands Cancer Institute (NKI), show that stable aneuploid tumor cells are more sensitive to small molecule inhibitors of TTK than chromosome instable cells. Chromosomal instability is a hallmark of cancer and one of the main causes of “aneuploidy”, a state of an imbalanced chromosome number. The protein kinase TTK, commonly referred to as Mps1, is a component of the spindle assembly checkpoint, a surveillance mechanism that controls the fidelity of chromosome segregation. High levels of TTK correlate with chromosomal instability in several aggressive cancers, such as breast cancer and hepatocellular carcinoma. To determine the relationship between chromosomal instability and sensitivity to TTK inhibitors, Dr. Marion Libouban from NTRC investigated the effect of TTK inhibition on cancer cells with abnormal chromosomal states using karyotype analysis and time-lapse microscopy at NKI. Time-lapse imaging is a live cell imaging technique that allows visualization of the mitotic timing and chromosomal mis-segregation during the metaphase to anaphase transition.
Taking advantage of the selective and sub-nanomolar potent TTK inhibitor NTRC 0066-0, which was developed by NTRC {link to article in Annals of Oncology}, Libouban showed that inhibition of TTK overrides the mitotic checkpoint, irrespective of cell line sensitivity. In stable aneuploid cells, such as the colorectal adenocarcinoma cell line LoVo (see photograph), NTRC 0066-0 induced acute chromosomal instability. In contrast, in cells with high levels of pre-existing chromosomal instability there was only a small additional fraction of cells mis-segregating their chromosomes. In proliferation assays stable aneuploid cells were more sensitive than cell lines with pre-existing chromosomal instability.
NTRC 0066-0 induces massive chromosome mis-segregation in LoVo cells. The left panel shows vehicle-treated cells as control.
In collaboration with Prof. Dr. Zuzana Storchova from the Technical University Kaiserslautern (Germany), Libouban and colleagues investigated the effect of TTK inhibitors on post-tetraploid cancer cells. Tetraploids are thought to be an intermediate between diploid and unstable aneuploid cells. More than a third of human cancers went through tetraploidy during tumorigenesis. NTRC scientists, in collaboration with Prof. Storchova, have previously shown that post-tetraploids are more resistant to multiple cytotoxic drugs and targeted agents {link to article in Cell Cycle}. Remarkably, as shown in the Oncotarget article, TTK inhibitors had the same potency on post-tetraploid and parental diploid cells, suggesting that TTK targeting may be a better choice for the eradication of tumor cells that underwent whole genome doubling than other drugs interfering with mitosis.
For the first time, the effect of a TTK inhibitor on the viability and proliferation of primary human patient-derived tumor cell samples and organoids was studied. NTRC 0066-0 inhibited the proliferation of patient-derived colorectal cancer organoids with a potency similar to that of cancer cell lines. In contrast, NTRC 0066-0 did not reduce the viability of non-proliferating T cell acute lymphoblastic leukemia cell samples. Consequently, TTK inhibitor therapy is expected to spare non-dividing cells, and may be used to target chromosomally stable aneuploid tumors.
To access the article follow: link to Oncotarget
The study was performed in the frame-work of the European Commission-funded FP7 Marie Curie International Training Network project “PloidyNet”
About NTRC
NTRC is a precision medicine company dedicated to the development of new anti-cancer drugs. NTRC facilitates the development of novel therapies by providing cancer cell line profiling services (Oncolines™, OncolinesProfiler™, and SynergyFinder™) and target residence time measurements for protein kinases (ResidenceTimer™) on a fee-for-service basis. NFK GreenScreen™, an assay read-out for the cancer immunotherapy drug targets IDO1 and TDO, is supplied to clients globally. For more information please visit www.ntrc.nl or contact info@ntrc.nl
