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1.
Proc Natl Acad Sci U S A ; 115(7): E1570-E1577, 2018 02 13.
Article in English | MEDLINE | ID: mdl-29378962

ABSTRACT

TTK protein kinase (TTK), also known as Monopolar spindle 1 (MPS1), is a key regulator of the spindle assembly checkpoint (SAC), which functions to maintain genomic integrity. TTK has emerged as a promising therapeutic target in human cancers, including triple-negative breast cancer (TNBC). Several TTK inhibitors (TTKis) are being evaluated in clinical trials, and an understanding of the mechanisms mediating TTKi sensitivity and resistance could inform the successful development of this class of agents. We evaluated the cellular effects of the potent clinical TTKi CFI-402257 in TNBC models. CFI-402257 induced apoptosis and potentiated aneuploidy in TNBC lines by accelerating progression through mitosis and inducing mitotic segregation errors. We used genome-wide CRISPR/Cas9 screens in multiple TNBC cell lines to identify mechanisms of resistance to CFI-402257. Our functional genomic screens identified members of the anaphase-promoting complex/cyclosome (APC/C) complex, which promotes mitotic progression following inactivation of the SAC. Several screen candidates were validated to confer resistance to CFI-402257 and other TTKis using CRISPR/Cas9 and siRNA methods. These findings extend the observation that impairment of the APC/C enables cells to tolerate genomic instability caused by SAC inactivation, and support the notion that a measure of APC/C function could predict the response to TTK inhibition. Indeed, an APC/C gene expression signature is significantly associated with CFI-402257 response in breast and lung adenocarcinoma cell line panels. This expression signature, along with somatic alterations in genes involved in mitotic progression, represent potential biomarkers that could be evaluated in ongoing clinical trials of CFI-402257 or other TTKis.


Subject(s)
Anaphase-Promoting Complex-Cyclosome/metabolism , Cell Cycle Proteins/antagonists & inhibitors , Drug Resistance, Neoplasm , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Triple Negative Breast Neoplasms/enzymology , Anaphase-Promoting Complex-Cyclosome/genetics , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Female , Genomic Instability/drug effects , Humans , Mitosis/drug effects , Protein Serine-Threonine Kinases/metabolism , Protein-Tyrosine Kinases/metabolism , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/physiopathology
2.
Leukemia ; 31(10): 2029-2036, 2017 10.
Article in English | MEDLINE | ID: mdl-28167833

ABSTRACT

Risk stratification of acute myeloid leukemia (AML) patients needs improvement. Several AML risk classification models based on somatic mutations or gene-expression profiling have been proposed. However, systematic and independent validation of these models is required for future clinical implementation. We performed whole-transcriptome RNA-sequencing and panel-based deep DNA sequencing of 23 genes in 274 intensively treated AML patients (Clinseq-AML). We also utilized the The Cancer Genome Atlas (TCGA)-AML study (N=142) as a second validation cohort. We evaluated six previously proposed molecular-based models for AML risk stratification and two revised risk classification systems combining molecular- and clinical data. Risk groups stratified by five out of six models showed different overall survival in cytogenetic normal-AML patients in the Clinseq-AML cohort (P-value<0.05; concordance index >0.5). Risk classification systems integrating mutational or gene-expression data were found to add prognostic value to the current European Leukemia Net (ELN) risk classification. The prognostic value varied between models and across cohorts, highlighting the importance of independent validation to establish evidence of efficacy and general applicability. All but one model replicated in the Clinseq-AML cohort, indicating the potential for molecular-based AML risk models. Risk classification based on a combination of molecular and clinical data holds promise for improved AML patient stratification in the future.


Subject(s)
Gene Expression Profiling , Leukemia, Myeloid, Acute/genetics , Models, Biological , Risk Assessment/methods , Sequence Analysis, DNA , Transcriptome , Adolescent , Adult , Aged , Aged, 80 and over , Bone Marrow/chemistry , Cohort Studies , DNA Mutational Analysis , DNA, Neoplasm/genetics , Female , Humans , Karyotyping , Leukemia, Myeloid, Acute/classification , Male , Microarray Analysis , Middle Aged , Prognosis , RNA, Messenger/genetics , RNA, Neoplasm/genetics , Young Adult
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