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Cyclin-dependent kinase 9 (CDK9) is a novel prognostic marker and therapeutic target in ovarian cancer.

ABSTRACT: Despite surgical and chemotherapeutic advances over the past few decades, the prognosis for ovarian cancer remains very poor. Although cyclin-dependent kinase (CDK) 9 has an established pathogenic role in various cancers, its function in ovarian cancer remains poorly defined. The purpose of this study was to evaluate the expression of CDK9 and its therapeutic potential in ovarian cancer. CDK9 expression was determined by immunohistochemistry in a unique ovarian cancer tissue microarray constructed with paired primary, metastatic, and recurrent tumor tissues from 26 ovarian cancer patients. CDK9 was highly expressed in human ovarian cancer cell lines and was also elevated in metastatic and recurrent ovarian tumor tissue compared with patient-matched primary ovarian tumor tissue. In addition, increased CDK9 significantly correlated with poor patient prognosis. Inhibition of CDK9 by small interfering RNA or CDK9 inhibitor functionally suppressed RNA transcription elongation, induced apoptosis, and reduced proliferation of ovarian cancer cells. Inhibition of CDK9 also suppressed ovarian cancer cell spheroid growth, clonogenicity formation, and migration activity. Our results reveal CDK9 as a novel prognostic biomarker and a promising therapeutic target for preventing metastasis and recurrence while also improving the overall clinical outcome for ovarian cancer patients.-Wang, J., Dean, D. C., Hornicek, F. J., Shi, H., Duan, Z. Cyclin-dependent kinase 9 (CDK9) is a novel prognostic marker and therapeutic target in ovarian cancer.

SUBMITTER: Wang J

PROVIDER: S-EPMC6463912 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:RON (MST1R) is one of two members of the MET receptor tyrosine kinase family, along with parent receptor MET. RON has a putative role in several cancers, but its expression and function is poorly characterized in gastroesophageal adenocarcinoma. A recognized functional role of MET tyrosine kinase in gastroesophageal cancer has led to early phase clinical trials using MET inhibitors, with unimpressive results. Therefore, the role of RON in gastroesophageal cancer, as well as its role in cooperative signaling with MET and as a mechanism of resistance to MET inhibition, was studied in gastroesophageal tissues and cell lines. By IHC, RON was highly over-expressed in 74% of gastroesophageal samples (n=94), and over-expression was prognostic of poor survival (p=0.008); RON and MET co-expression occurred in 43% of samples and was prognostic of worst survival (p=0.03). High MST1R gene copy number by quantitative polymerase chain reaction, and confirmed by fluorescence in situ hybridization and/or array comparative genomic hybridization, was seen in 35.5% (16/45) of cases. High MST1R gene copy number correlated with poor survival (p=0.01), and was associated with high MET and ERBB2 gene copy number. A novel somatic MST1R juxtamembrane mutation R1018G was found in 11% of samples. RON signaling was functional in cell lines, activating downstream effector STAT3, and resulted in increased viability over controls. RON and MET co-stimulation assays led to enhanced malignant phenotypes over stimulation of either receptor alone. Growth inhibition as evidenced by viability and apoptosis assays was optimal using novel blocking monoclonal antibodies to both RON and MET, versus either alone. SU11274, a classic MET small molecule tyrosine kinase inhibitor, blocked signaling of both receptors, and proved synergistic when combined with STAT3 inhibition (combination index < 1). These preclinical studies define RON as an important novel prognostic marker and therapeutic target for gastroesophageal cancer warranting further investigation.

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Cyclin-dependent kinase 9 (CDK9) is a novel prognostic marker and therapeutic target in ovarian cancer.

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