Oss, October, 16th, 2017 – NTRC will present three scientific posters at the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics conference to be held in Philadelphia (USA) from October 27th to 30th. Two of the posters concern pharmacogenomic analysis of cell proliferation data, one related to NTRC’s TTK kinase inhibitor program; the other on gene expression analysis by GeneNominator™.
Screening of new drugs on large cell panels is an important tool to study the biological mechanism of drug response. NTRC scientists have previously shown that the workflow of Oncolines™ screening leads to highly reproducible IC50s which are necessary for genomic biomarker discovery [1,2]. The IC50 in Oncolines™ profiling experiment have been coupled to curated databases of somatic mutations and copy numbers . However, these changes reflect only a small percentage of oncogenic transformations. A more comprehensive view of oncogenic signalling can be obtained from mRNA expression levels . A workflow to investigate drug response in the 102 cell line Oncolines™ panel based on gene expression levels was developed at NTRC, and applied to determine correlations between cancer cell line sensitivity and gene expression levels of more than 18,000 genes. At the AACR-NCI-EORTC conference case studies will be presented on a protein – protein interaction inhibitor, irreversible EGFR and BTK kinase inhibitors, and drug transporter substrates.
Genomic drug sensitivity biomarker for TTK inhibitors
The spindle assembly checkpoint TTK, also known as Mps1, is a key regulator of chromosome segregation and a promising new drug target for the treatment of cancer. With the aim to identify a genomic biomarker to predict the response of tumour cells to TTK inhibitor therapy, a set of TTK inhibitors from different chemical series  was profiled on the Oncolines™ cell line panel . Cell lines harbouring activating mutations in the CTNNB1 gene, encoding the Wnt pathway signalling regulator β-catenin, were up to five times more sensitive to TTK inhibitors than cell lines wild-type for CTNNB1 . The association of CTNNB1-mutant status and increased cancer cell line sensitivity to TTK inhibition was confirmed with isogenic cell line pairs harbouring either mutant or wild-type CTNNB1. Treatment of a xenograft model of a CTNNB1-mutant cell line with NTRC 1501-0 resulted into tumour regression. Based on these results, mutant CTNNB1 has been proposed as a prognostic drug response biomarker, enabling the selection of patients most likely to respond to TTK inhibitor therapy in proof-of-concept clinical trials
Combining cell panel screening with analysis of gene expression levels reveals features of drug response and resistance, by Dr. Joost Uitdehaag
Session: Therapeutic Agents: Small-Molecule Kinase Inhibitors; Sunday Oct 29, 2017 12:30 PM – 4:00 PM; Poster Board Number 155, Abstract Number B155
TTK inhibitors as a targeted therapy for CTNNB1 (β-catenin) mutant cancers, by Dr. Guido Zaman
Session: New Molecular Targets; Sunday Oct 29, 2017 12:30 PM – 4:00 PM; Poster Board Number 65, Abstract Number B065
Novel synergistic drug combinations of PARP, bromodomain, and spindle assembly checkpoint kinase inhibitors by large-scale screen of 150 anticancer agents, by Dr. Suzanne van Gerwen
Session: Drug Screening; Saturday Oct 28, 2017 12:30 PM – 4:00 PM; Poster Board Number 153, Abstract Number A153
Meet NTRC Services at booth #815 in the Exhibition Hall of the Pennsylvania Convention Center
 Uitdehaag et al. (2016) Cell panel profiling reveals conserved therapeutic clusters and differentiates the mechanism of action of different PI3K/mTOR, Aurora kinase and EZH2 inhibitors. Molecular Cancer Therapeutics 15, 3097-3109.
 Zaman et al. (2017) TTK inhibitors as a targeted therapy for CTNNB1 (β-catenin) mutant cancers. Molecular Cancer Therapeutics, advanced online, July 27, 2017.
 Rees et al. (2016) Correlating chemical sensitivity and basal gene expression reveals mechanism of action. Nature Chemical Biology 12: 109-116.
 Uitdehaag et al. (2017) Target residence time-guided optimization on TTK kinase results in inhibitors with potent anti-proliferative activity. Journal of Molecular Biology, 429, 2211-2230.
 de Roos et al. Prognostic biomarkers for TTK inhibitor chemotherapy. WO 2016/166255 A1.
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™, SynergyFinder™ and SynergyScreen™) 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. NTRC has internal drug discovery programs on TTK, IDO1 and TDO. For more information please visit www.ntrc.nl or contact [email protected]