31-07-2017

Genomic drug sensitivity biomarker for TTK inhibitors published in Molecular Cancer Therapeutics

In a new publication, NTRC scientists propose mutations in the cancer hot spot region of the β-catenin gene (CTNNB1) as prognostic drug sensitivity biomarkers for TTK inhibitors. The paper appeared online today in the journal Molecular Cancer Therapeutics, a leading journal on cancer research from the American Association of Cancer Research (AACR).

The protein kinase TTK, also known as Mps1, is a promising new drug target. Inhibition of TTK activity with small molecule inhibitors effectively kills tumor cells, and several TTK inhibitors have been shown to reduce the growth of tumors in in vivo models of cancer. While the first TTK inhibitors have entered phase 1 dose escalating studies in combination with taxane chemotherapy, a patient stratification strategy was still missing. With the aim to identify a genomic biomarker to predict the response of tumor cells to TTK inhibitor therapy, NTRC scientists profiled a set of pre-clinical and clinical TTK inhibitors from different chemical series on the Oncolines™ cancer cell line panel. Oncolines™ are proliferation assays on a large panel of genetically characterized cell lines derived from different tumors. As shown in the article in Molecular Cancer Therapeutics, cell lines harboring activating mutations in the CTNNB1 gene were on average up to five times more sensitive to TTK inhibitors than cell lines wild-type for CTNNB1. The mutations are located in a so-called ‘cancer hot spot’, a region frequently mutated in human tumours. The mutations cause β-catenin to become an oncogene. In the article, it is outlined how these mutations make cancer cell lines more dependent on TTK.

The association of CTNNB1 mutant status and increased cancer cell line sensitivity to TTK inhibition was confirmed by gene expression analysis using GeneNominator™. NTRC scientists translated these findings to an in vivo cancer model: Treatment of a xenograft model of a CTNNB1 mutant cell line with the TTK inhibitor NTRC 0066-0 resulted in complete inhibition of tumor growth.

The discovery that mutant CTNNB1 is a prognostic drug response biomarker for TTK inhibitors will enable the selection of patients most likely to respond to TTK inhibitor therapy in proof-of-principle clinical trials. Mutations in the CTNNB1 gene occur at high frequency in endometrial cancer (30%) and hepatocellular carcinoma (27%), which is known to express high levels of TTK. Interestingly, β-catenin signaling has also been implicated in intrinsic resistance against immunotherapy in melanoma by regulation of T cell infiltration. Thus, new areas of potential clinical application of TTK inhibitor drugs have been uncovered by Oncolines™ profiling.

Oncolines™ and GeneNominator™ are offered as commercial services to customers worldwide by NTRC.

To access the article, follow this link.

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