Aberrant CDK9 expression within chordoma tissues and the therapeutic potential of a selective CDK9 inhibitor LDC000067

Abstract

Objectives: Chordomas are slow-growing malignancies that commonly affect vital neurological structures. These neoplasms are highly resistant to current chemotherapeutic regimens and often recur after surgical intervention. Therefore, there is an urgent need to identify molecular targets and more robust drugs to improve chordoma patient outcomes. It is well accepted that cyclin-dependent protein kinase 9 (CDK9) has tumorigenic roles in various cancers; however, the expression and significance of CDK9 in chordoma remains unknown. Methods: Expression of CDK9 in chordoma cell lines and tumor tissues was examined by Western blot and immunohistochemistry (IHC). The correlation between CDK9 expression in patient tissues and clinical prognosis was analyzed. The functional roles of CDK9 in chordoma were investigated after the addition of small interfering RNA (siRNA) and CDK9 inhibitor (LDC000067). Cell growth and proliferation were assessed with MTT and clonogenic assays. The effect of CDK9 inhibition on chordoma cells was further evaluated with a three-dimensional (3D) cell culture model which mimics the in vivo environment. Results: CDK9 was expressed in both chordoma cell lines and chordoma tissues. High-expression of CDK9 correlated with recurrence and poor outcomes for chordoma patients. CDK9 silencing with siRNA decreased growth and proliferation of chordoma cells and lowered levels of Mcl-1 and RNA polymerase II (RNAP II) phosphorylation. Pharmacological inhibition of CDK9 with the small molecular inhibitor LDC000067 reduced cell growth, supported apoptosis, suppressed cell colony formation in a clonogenic assay, and decreased spheroid growth in 3D culture. Conclusion: We demonstrate that CDK9 expression in chordoma correlates with patient outcome, and, when inhibited, chordoma cell growth and proliferation significantly decreases. Taken together, these results support CDK9 as an emerging potential target in chordoma therapy.

T‐LAK cell‐originated protein kinase (TOPK) is a Novel Prognostic and Therapeutic Target in Chordoma

“…The tissue microarray (TMA) was constructed from 55 individual chordoma patient specimens within a formalin-fixed paraffin-embedded (FFPE) block as previously described. 23,24 The clinicopathological characteristics of the specimens were collected and are outlined in Table 1, including age, gender, tumour location, recurrence, metastasis and disease status. The samples included 39 (70.9%) males and 16 (29.1%) females with an average age of 58.9 years old (range: 25-88 years old).…”

Temperature-Sensitive Lipid-Coated Carbon Nanotubes for Synergistic Photothermal Therapy and Gene Therapy

“…Gene therapy (GT), which uses nucleic acids to treat tumors, is considered a promising therapeutic strategy. − In particular, small-interfering RNAs (siRNAs) have attracted great attention as potential therapeutic agents, because they can regulate protein expression by silencing mRNA (mRNA). , Despite the treatment potential of siRNAs, they have notable limitations, such as fast enzymatic degradation and low intracellular uptake rate in vivo , which necessitate the improvement in delivery to the target. In addition, RNA, owing to its strong negative charge, faces an electrostatic barrier against internalization by cells, which further hinders its therapeutic efficacy in vivo . − Therefore, the combination of GT with other therapeutic methods is considered necessary to compensate for its inherent disadvantages.…”

Prognostic Impact of Caspase-8, CDK9 and Phospho-CDK9 (Thr 186) Expression in Patients with Uterine Cervical Cancer Treated with Definitive Chemoradiation and Brachytherapy

“…As for caspase-8, the prognostic/predictive value of CDK9, however, still remains controversial among different tumor types. Whereas some authors have indicated that high levels of CDK9 expression in patients with pancreatic adenocarcinoma are associated with significantly shortened OS, especially in well differentiated tumors [ 36 , 41 , 42 ], others have demonstrated that higher CDK9 expression is associated with significantly improved survival [ 43 , 44 ].…”