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Ref Type Journal Article
PMID (28751540)
Authors Zaman GJR, de Roos JADM, Libouban MAA, Prinsen MBW, de Man J, Buijsman RC, Uitdehaag JCM
Title TTK Inhibitors as a Targeted Therapy for CTNNB1 (β-catenin) Mutant Cancers.
Journal Vol Issue Date Pages Journal Short Title
Molecular cancer therapeutics 16 11 2017 Nov 2609-2617 Mol Cancer Ther
URL
Abstract Text The spindle assembly checkpoint kinase TTK (Mps1) is a key regulator of chromosome segregation and is the subject of novel targeted therapy approaches by small-molecule inhibitors. Although the first TTK inhibitors have entered phase I dose escalating studies in combination with taxane chemotherapy, a patient stratification strategy is still missing. With the aim to identify a genomic biomarker to predict the response of tumor cells to TTK inhibitor therapy, we profiled a set of preclinical and clinical TTK inhibitors from different chemical series on a panel of 66 genetically characterized cell lines derived from different tumors (Oncolines). Cell lines harboring activating mutations in the CTNNB1 gene, encoding the Wnt pathway signaling regulator β-catenin, were on average 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 harboring either mutant or wild-type CTNNB1 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. Mutations in CTNNB1 occur at relatively high frequency in endometrial cancer and hepatocellular carcinoma, which are known to express high TTK levels. We propose mutant CTNNB1 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. Mol Cancer Ther; 16(11); 2609-17. ©2017 AACR.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
CTNNB1 S45F colorectal adenocarcinoma predicted - sensitive BAY1217389 Preclinical - Cell culture Actionable In a preclinical study, cell lines harboring CTNNB1 hotspot mutations, including a colorectal adenocarcinoma cell line harboring CTNNB1 S45F, demonstrated increased sensitivity to BAY1217389 compared to cell lines with wild-type CTNNB1 in culture (PMID: 28751540). 28751540
CTNNB1 S45del colon carcinoma predicted - sensitive MPI-0479605 Preclinical - Cell culture Actionable In a preclinical study, cell lines harboring CTNNB1 hotspot mutations, including a colon carcinoma cell line harboring CTNNB1 S45del demonstrated increased sensitivity to MPI-0479605 compared to cell lines with wild-type CTNNB1 in culture (PMID: 28751540). 28751540
CTNNB1 S33Y colorectal adenocarcinoma predicted - sensitive NMS-P715 Preclinical - Cell culture Actionable In a preclinical study, cell lines harboring CTNNB1 hotspot mutations, including a colorectal adenocarcinoma cell line harboring CTNNB1 S33Y, demonstrated increased sensitivity to NMS-P715 compared to cell lines with wild-type CTNNB1 in culture (PMID: 28751540). 28751540
CTNNB1 S33Y colorectal adenocarcinoma predicted - sensitive Mps1-IN-1 Preclinical - Cell culture Actionable In a preclinical study, cell lines harboring CTNNB1 hotspot mutations, including a colorectal adenocarcinoma cell line harboring CTNNB1 S33Y demonstrated increased sensitivity to Mps1-IN-1 compared to cell lines with wild-type CTNNB1 in culture (PMID: 28751540). 28751540
CTNNB1 S45del colon carcinoma predicted - sensitive BAY1161909 Preclinical - Cell culture Actionable In a preclinical study, cell lines harboring CTNNB1 hotspot mutations, including a colon carcinoma cell line harboring CTNNB1 S45del, demonstrated increased sensitivity to BAY1161909 compared to cell lines with wild-type CTNNB1 in culture (PMID: 28751540). 28751540
CTNNB1 S33Y colorectal adenocarcinoma predicted - sensitive BAY1161909 Preclinical - Cell culture Actionable In a preclinical study, cell lines harboring CTNNB1 hotspot mutations, including a colorectal adenocarcinoma cell line harboring CTNNB1 S33Y, demonstrated increased sensitivity to BAY1161909 compared to cell lines with wild-type CTNNB1 in culture (PMID: 28751540). 28751540
CTNNB1 S45del colon carcinoma predicted - sensitive NMS-P715 Preclinical - Cell culture Actionable In a preclinical study, cell lines harboring CTNNB1 hotspot mutations, including a colon carcinoma cell line harboring CTNNB1 S45del, demonstrated increased sensitivity to NMS-P715 compared to cell lines with wild-type CTNNB1 in culture (PMID: 28751540). 28751540
CTNNB1 S33Y colorectal adenocarcinoma predicted - sensitive Mps-BAY2b Preclinical - Cell culture Actionable In a preclinical study, cell lines harboring CTNNB1 hotspot mutations, including a colorectal adenocarcinoma cell line harboring CTNNB1 S33Y, demonstrated increased sensitivity to Mps-BAY2b compared to cell lines with wild-type CTNNB1 in culture (PMID: 28751540). 28751540
CTNNB1 S45F colorectal adenocarcinoma predicted - sensitive NMS-P715 Preclinical - Cell culture Actionable In a preclinical study, cell lines harboring CTNNB1 hotspot mutations, including a colorectal adenocarcinoma cell line harboring CTNNB1 S45F, demonstrated increased sensitivity to NMS-P715 compared to cell lines with wild-type CTNNB1 in culture (PMID: 28751540). 28751540
CTNNB1 T41A lung cancer predicted - sensitive BAY1217389 Preclinical - Cell culture Actionable In a preclinical study, cell lines harboring CTNNB1 hotspot mutations, including a lung cancer cell line harboring CTNNB1 T41A, demonstrated increased sensitivity to BAY1217389 compared to cell lines with wild-type CTNNB1 in culture (PMID: 28751540). 28751540
CTNNB1 S45F colorectal adenocarcinoma predicted - sensitive Mps-BAY2b Preclinical - Cell culture Actionable In a preclinical study, cell lines harboring CTNNB1 hotspot mutations, including a colorectal adenocarcinoma cell line harboring CTNNB1 S45F, demonstrated increased sensitivity to Mps-BAY2b compared to cell lines with wild-type CTNNB1 in culture (PMID: 28751540). 28751540
CTNNB1 S45del colon carcinoma predicted - sensitive NTRC 0066-0 Preclinical - Cell culture Actionable In a preclinical study, cell lines harboring CTNNB1 hotspot mutations, including a colon carcinoma cell line harboring CTNNB1 S45del, demonstrated increased sensitivity to NTRC 0066-0 compared to cell lines with wild-type CTNNB1 or an isogenic cell line lacking the CTNNB1 mutation, in culture (PMID: 28751540). 28751540
CTNNB1 S45F colorectal adenocarcinoma predicted - sensitive NTRC 0066-0 Preclinical - Cell culture Actionable In a preclinical study, cell lines harboring CTNNB1 hotspot mutations, including a colorectal carcinoma cell line harboring CTNNB1 S45F, demonstrated increased sensitivity to NTRC 0066-0 compared to cell lines with wild-type CTNNB1 in culture (PMID: 28751540). 28751540
CTNNB1 S33Y colorectal adenocarcinoma predicted - sensitive BAY1217389 Preclinical - Cell culture Actionable In a preclinical study, cell lines harboring CTNNB1 hotspot mutations, including a colorectal adenocarcinoma cell line harboring CTNNB1 S33Y, demonstrated increased sensitivity to BAY1217389 compared to cell lines with wild-type CTNNB1 in culture (PMID: 28751540). 28751540
CTNNB1 S45del colon carcinoma predicted - sensitive Mps-BAY2b Preclinical - Cell culture Actionable In a preclinical study, cell lines harboring CTNNB1 hotspot mutations, including a colon carcinoma cell line harboring CTNNB1 S45del, demonstrated increased sensitivity to Mps-BAY2b compared to cell lines with wild-type CTNNB1 in culture (PMID: 28751540). 28751540
CTNNB1 T41A lung cancer predicted - sensitive MPI-0479605 Preclinical - Cell culture Actionable In a preclinical study, cell lines harboring CTNNB1 hotspot mutations, including a lung cancer cell line harboring CTNNB1 T41A demonstrated increased sensitivity to MPI-0479605 compared to cell lines with wild-type CTNNB1 in culture (PMID: 28751540). 28751540
CTNNB1 T41A lung cancer predicted - sensitive Mps-BAY2b Preclinical - Cell culture Actionable In a preclinical study, cell lines harboring CTNNB1 hotspot mutations, including a lung cancer cell line harboring CTNNB1 T41A, demonstrated increased sensitivity to Mps-BAY2b compared to cell lines with wild-type CTNNB1 in culture (PMID: 28751540). 28751540
CTNNB1 S45del colon carcinoma predicted - sensitive BAY1217389 Preclinical - Cell culture Actionable In a preclinical study, cell lines harboring CTNNB1 hotspot mutations, including a colon carcinoma cell line harboring CTNNB1 S45del, demonstrated increased sensitivity to BAY1217389 compared to cell lines with wild-type CTNNB1 in culture (PMID: 28751540). 28751540
CTNNB1 T41A lung cancer predicted - sensitive BAY1161909 Preclinical - Cell culture Actionable In a preclinical study, cell lines harboring CTNNB1 hotspot mutations, including a lung cancer cell line harboring CTNNB1 T41A, demonstrated increased sensitivity to BAY1161909 compared to cell lines with wild-type CTNNB1 in culture (PMID: 28751540). 28751540
CTNNB1 T41A lung cancer predicted - sensitive NTRC 0066-0 Preclinical - Cell line xenograft Actionable In a preclinical study, cell lines harboring CTNNB1 hotspot mutations, including a lung cancer cell line harboring CTNNB1 T41A, demonstrated increased sensitivity to NTRC 0066-0 compared to cell lines with wild-type CTNNB1, in culture and in xenograft models (PMID: 28751540). 28751540
CTNNB1 S33Y colorectal adenocarcinoma predicted - sensitive MPI-0479605 Preclinical - Cell culture Actionable In a preclinical study, cell lines harboring CTNNB1 hotspot mutations, including a colorectal adenocarcinoma cell line harboring CTNNB1 S33Y demonstrated increased sensitivity to MPI-0479605 compared to cell lines with wild-type CTNNB1 in culture (PMID: 28751540). 28751540
CTNNB1 T41A lung cancer predicted - sensitive NMS-P715 Preclinical - Cell culture Actionable In a preclinical study, cell lines harboring CTNNB1 hotspot mutations, including a lung cancer cell line harboring CTNNB1 T41A, demonstrated increased sensitivity to NMS-P715 compared to cell lines with wild-type CTNNB1 in culture (PMID: 28751540). 28751540
CTNNB1 T41A lung cancer predicted - sensitive Mps1-IN-1 Preclinical - Cell culture Actionable In a preclinical study, cell lines harboring CTNNB1 hotspot mutations, including a lung cancer cell line harboring CTNNB1 T41A, demonstrated increased sensitivity to Mps1-IN-1 compared to cell lines with wild-type CTNNB1 in culture (PMID: 28751540). 28751540
CTNNB1 S45F colorectal adenocarcinoma predicted - sensitive Mps1-IN-1 Preclinical - Cell culture Actionable In a preclinical study, cell lines harboring CTNNB1 hotspot mutations, including a colorectal adenocarcinoma cell line harboring CTNNB1 S45F demonstrated increased sensitivity to Mps1-IN-1 compared to cell lines with wild-type CTNNB1 in culture (PMID: 28751540). 28751540
CTNNB1 S45del colorectal adenocarcinoma predicted - sensitive BAY1161909 Preclinical - Cell culture Actionable In a preclinical study, cell lines harboring CTNNB1 hotspot mutations, including a colorectal adenocarcinoma cell line harboring CTNNB1 S45del, demonstrated increased sensitivity to BAY1161909 compared to cell lines with wild-type CTNNB1 in culture (PMID: 28751540). 28751540
CTNNB1 S45del colon carcinoma predicted - sensitive Mps1-IN-1 Preclinical - Cell culture Actionable In a preclinical study, cell lines harboring CTNNB1 hotspot mutations, including a colon carcinoma cell line harboring CTNNB1 S45del, demonstrated increased sensitivity to Mps1-IN-1 compared to cell lines with wild-type CTNNB1 in culture (PMID: 28751540). 28751540
CTNNB1 S33Y colorectal adenocarcinoma predicted - sensitive NTRC 0066-0 Preclinical - Cell culture Actionable In a preclinical study, cell lines harboring CTNNB1 hotspot mutations, including a colorectal carcinoma cell line harboring CTNNB1 S33Y, demonstrated increased sensitivity to NTRC 0066-0 compared to cell lines with wild-type CTNNB1 in culture (PMID: 28751540). 28751540
CTNNB1 S45F colorectal adenocarcinoma predicted - sensitive MPI-0479605 Preclinical - Cell culture Actionable In a preclinical study, cell lines harboring CTNNB1 hotspot mutations, including a colorectal adenocarcinoma cell line harboring CTNNB1 S45F demonstrated increased sensitivity to MPI-0479605 compared to cell lines with wild-type CTNNB1 in culture (PMID: 28751540). 28751540