CDK9 is a prognostic marker and therapeutic target in pancreatic cancer

Abstract

Despite recent advances in diagnosis and therapy, prognosis of pancreatic cancer still remains very poor. Besides valid prognostic markers, novel therapeutic approaches are urgently needed. The family of cyclin-dependent kinases comprises 20 kinases which contribute to malignancy by promoting proliferation, migration, invasion, and apoptotic resistance of cancer cells. In this work, we investigated the role of CDK9 in pancreatic cancer. Immunohistochemical analysis of CDK9 expression in tumor and normal tissue of pancreatic cancer patients revealed an overexpression of CDK9 in pancreatic cancer tissue. In addition, high CDK9 expression in tumor tissue is associated with significantly shortened survival, especially in well-differentiated tumors. Moreover, the therapeutic potential of selective CDK9 inhibition on pancreatic cancer cells was evaluated by analysis of cell viability, long-term survival, and induction of apoptosis and characterized by western blotting and flow cytometry. Pharmacological CDK9 inhibition by SNS-032 drastically reduced cell viability in pancreatic cancer cells and potently suppressed long-term survival. Analyzing the mechanism of action revealed that CDK9 inhibition induced apoptosis and cell cycle arrest in a time-dependent manner by suppression of anti-apoptotic proteins. Furthermore, CDK9 inhibition potently enhances the therapeutic effect of chemotherapeutics in pancreatic cancer cells. In conclusion, we identified CDK9 as a negative prognostic marker in pancreatic cancer. Furthermore, pharmacological CDK9 inhibition is a novel and promising therapeutic approach for pancreatic cancer.

Targeting regulation of cyclin dependent kinase 9 as a novel therapeutic strategy in synovial sarcoma

“…Further analysis revealed that a high level of CDK9 expression was associated with a worse prognosis for sarcoma patients, whereas patients with lower CDK9 expression had a better prognosis intern of overall survival. Therefore, as reported for other cancer types, our findings confirm that the overexpression of CDK9 is associated with a poor patient prognosis . The function of CDK9 was also evaluated in vitro and ex vivo, with results showing that inhibition of CDK9 suppresses cell growth and proliferation, spheroid formation, and motility, while inducing apoptosis in synovial sarcoma cells.…”

CDK9 Expression Shows Role as a Potential Prognostic Biomarker in Breast Cancer Patients Who Fail to Achieve Pathologic Complete Response after Neoadjuvant Chemotherapy

“…Given that low CDK9 expression leads to increased spontaneous DNA damage and genetic instability, we speculate that patients with residual breast tumors with low CDK9 expression may have more aggressive disease and thus poorer prognoses. This paradoxical observation is in contrast to another study investigating CDK9 expression in patients with de novo pancreatic adenocarcinoma tumors, which showed that high CDK9 expression has worse clinical outcome [ 21 ] as well as its current investigation as a therapeutic target for cancer treatment [ 22 – 25 ].…”

Synthesis and Anti-Proliferative Effects of Mono- and Bis-Purinomimetics Targeting Kinases

“…Similarly, among the most advanced CDK4 and CDK6 inhibitors, purinomimetics abemaciclib (LY2835219) [ 22 , 23 ] and ribociclib (LEE011) ( Figure 1 ) [ 23 , 48 ] showed to be potent CDK9 inhibitors. In addition, the therapeutic potential of selective CDK inhibition on pancreatic cancer cells was revealed by other structurally related small molecule CDK inhibitor, dinaciclib (SCH727965) ( Figure 1 ) [ 21 , 49 ]. Furthermore, PASS analysis also revealed that some of selected compounds could potentially inhibit p38 MAP kinase with higher (compound 6b ) or lower probability (compound 4g ) ( Tables S4–S6 ).…”