Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endometrial carcinoma (EC) is the most common gynecologic malignancy in the United States, with limited effective targeted therapies. Endometrial tumors exhibit frequent alterations in protein kinases, yet only a small fraction of the kinome has been therapeutically explored. To identify kinase therapeutic avenues for EC, we profiled the kinome of endometrial tumors and normal endometrial tissues using Multiplexed Inhibitor Beads and Mass Spectrometry (MIB-MS). Our proteomics analysis identified a network of kinases overexpressed in tumors, including Serine/Arginine-Rich Splicing Factor Kinase 1 (SRPK1). Immunohistochemical (IHC) analysis of endometrial tumors confirmed MIB-MS findings and showed SRPK1 protein levels were highly expressed in endometrioid and uterine serous cancer (USC) histological subtypes. Moreover, querying large-scale genomics studies of EC tumors revealed high expression of SRPK1 correlated with poor survival. Loss-of-function studies targeting SRPK1 in an established USC cell line demonstrated SRPK1 was integral for RNA splicing, as well as cell cycle progression and survival under nutrient deficient conditions. Profiling of USC cells identified a compensatory response to SRPK1 inhibition that involved EGFR and the up-regulation of IGF1R and downstream AKT signaling. Co-targeting SRPK1 and EGFR or IGF1R synergistically enhanced growth inhibition in serous and endometrioid cell lines, representing a promising combination therapy for EC.
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PMID:Kinome Profiling of Primary Endometrial Tumors Using Multiplexed Inhibitor Beads and Mass Spectrometry Identifies SRPK1 as Candidate Therapeutic Target. 3299 15

Programmed death ligand 1 (PD-L1) protein expression is a proposed predictive biomarker of immunotherapy; thus, identification of the clinicopathological and molecular characteristics associated with PD-L1 expression is important and necessary. We examined PD-L1 immunohistochemical expression and its relationships with the clinicopathological and molecular characteristics of patients with surgically resected non-small cell lung carcinoma. PD-L1 expression differed according to the histological subtype. Among 633 patients with adenocarcinoma, 523 (82.6%) had no PD-L1 expression, 78 (12.3%) low expression and 32 (5.1%) high expression. PD-L1 expression was more common in males (p<0.001), smokers (p=0.002) and in patients with a more advanced stage (p=0.002), the solid predominant subtype (p<0.001), no EGFR mutations (p<0.001), a high MIB-1 labeling index (p<0.001) and positive p53 immunohistochemical expression (p<0.001). In a multivariate logistic regression analysis, the solid predominant subtype (OR=4.92, 95% CI: 2.72-8.89, p<0.001), no EGFR mutations (OR=2.27, 95% CI: 1.35-2.7, p=0.002), a high MIB-1 labeling index (OR=2.78, 95% CI: 1.72-4.55, p<0.001) and p53 positivity (OR=2.13, 95% CI:1.34-4.36, p=0.042) were significantly and independently associated with PD-L1 expression. The combination of the solid predominant subtype with a high MIB-1 labeling index was strongly associated with positive expression of PD-L1. In the 193 patients with squamous cell carcinoma, 92 (47.7%) had no PD-L1 expression, 57 (29.5%) low expression and 44 (22.8%) high expression. There were no significant correlations between PD-L1 expression and the evaluated clinicopathological or molecular characteristics of these patients. These results, indicating associations of PD-L1 with various clinicopathological or molecular characteristics in adenocarcinoma but not squamous cell carcinoma, may be useful for selecting patients with a good response to immune checkpoint inhibitors.
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PMID:PD-L1 protein expression is positively correlated with the solid predominant subtype, high MIB-1 labeling index and p53 expression and negatively correlated with EGFR mutations in lung adenocarcinoma. 3315 65


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