Browsing by Subject "Protein-Tyrosine Kinases"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Selective inhibition of pancreatic ductal adenocarcinoma cell growth by the mitotic MPS1 kinase inhibitor NMS-P715
    (American Association for Cancer Research, 2014-02) Slee, Roger B.; Grimes, Brenda R.; Bansal, Ruchi; Gore, Jesse; Blackburn, Corinne; Brown, Lyndsey; Gasaway, Rachel; Jeong, Jaesik; Victorino, Jose; March, Keith L.; Colombo, Riccardo; Herbert, Brittney-Shea; Korc, Murray; Department of Medical and Molecular Genetics, IU School of Medicine
    Most solid tumors, including pancreatic ductal adenocarcinoma (PDAC), exhibit structural and numerical chromosome instability (CIN). Although often implicated as a driver of tumor progression and drug resistance, CIN also reduces cell fitness and poses a vulnerability that can be exploited therapeutically. The spindle assembly checkpoint (SAC) ensures correct chromosome-microtubule attachment, thereby minimizing chromosome segregation errors. Many tumors exhibit upregulation of SAC components such as MPS1, which may help contain CIN within survivable limits. Prior studies showed that MPS1 inhibition with the small molecule NMS-P715 limits tumor growth in xenograft models. In cancer cell lines, NMS-P715 causes cell death associated with impaired SAC function and increased chromosome missegregation. Although normal cells appeared more resistant, effects on stem cells, which are the dose-limiting toxicity of most chemotherapeutics, were not examined. Elevated expression of 70 genes (CIN70), including MPS1, provides a surrogate measure of CIN and predicts poor patient survival in multiple tumor types. Our new findings show that the degree of CIN70 upregulation varies considerably among PDAC tumors, with higher CIN70 gene expression predictive of poor outcome. We identified a 25 gene subset (PDAC CIN25) whose overexpression was most strongly correlated with poor survival and included MPS1. In vitro, growth of human and murine PDAC cells is inhibited by NMS-P715 treatment, whereas adipose-derived human mesenchymal stem cells are relatively resistant and maintain chromosome stability upon exposure to NMS-P715. These studies suggest that NMS-P715 could have a favorable therapeutic index and warrant further investigation of MPS1 inhibition as a new PDAC treatment strategy.
  • Thumbnail Image
    Item
    Whole-Exome Sequencing in Familial Parkinson Disease
    (The JAMA Network, 2016-01) Farlow, Janice L.; Robak, Laurie A.; Hetrick, Kurt; Bowling, Kevin; Boerwinkle, Eric; Coban-Akdemir, Zeynep H.; Gambin, Tomasz; Gibbs, Richard A.; Gu, Shen; Jain, Preti; Jankovic, Joseph; Jhangiani, Shalini; Kaw, Kaveeta; Lai, Dongbing; Lin, Hai; Ling, Hua; Liu, Yunlong; Lupski, James R.; Muzny, Donna; Porter, Paula; Pugh, Elizabeth; White, Janson; Doheny, Kimberly; Myers, Richard M.; Shulman, Joshua M.; Foroud, Tatiana; Department of Medical and Molecular Genetics, IU School of Medicine
    IMPORTANCE: Parkinson disease (PD) is a progressive neurodegenerative disease for which susceptibility is linked to genetic and environmental risk factors. OBJECTIVE: To identify genetic variants contributing to disease risk in familial PD. DESIGN, SETTING, AND PARTICIPANTS: A 2-stage study design that included a discovery cohort of families with PD and a replication cohort of familial probands was used. In the discovery cohort, rare exonic variants that segregated in multiple affected individuals in a family and were predicted to be conserved or damaging were retained. Genes with retained variants were prioritized if expressed in the brain and located within PD-relevant pathways. Genes in which prioritized variants were observed in at least 4 families were selected as candidate genes for replication in the replication cohort. The setting was among individuals with familial PD enrolled from academic movement disorder specialty clinics across the United States. All participants had a family history of PD. MAIN OUTCOMES AND MEASURES: Identification of genes containing rare, likely deleterious, genetic variants in individuals with familial PD using a 2-stage exome sequencing study design. RESULTS: The 93 individuals from 32 families in the discovery cohort (49.5% [46 of 93] female) had a mean (SD) age at onset of 61.8 (10.0) years. The 49 individuals with familial PD in the replication cohort (32.6% [16 of 49] female) had a mean (SD) age at onset of 50.1 (15.7) years. Discovery cohort recruitment dates were 1999 to 2009, and replication cohort recruitment dates were 2003 to 2014. Data analysis dates were 2011 to 2015. Three genes containing a total of 13 rare and potentially damaging variants were prioritized in the discovery cohort. Two of these genes (TNK2 and TNR) also had rare variants that were predicted to be damaging in the replication cohort. All 9 variants identified in the 2 replicated genes in 12 families across the discovery and replication cohorts were confirmed via Sanger sequencing. CONCLUSIONS AND RELEVANCE: TNK2 and TNR harbored rare, likely deleterious, variants in individuals having familial PD, with similar findings in an independent cohort. To our knowledge, these genes have not been previously associated with PD, although they have been linked to critical neuronal functions. Further studies are required to confirm a potential role for these genes in the pathogenesis of PD.