Targeting CDK9: A novel biomarker in�the�treatment of endometrial cancer

Abstract

Endometrial cancer is one of the three major malignant tumors of the female reproductive system. Although cyclin-dependent kinase 9 (CDK9) has a definitive pathogenic role in various types of cancer, little is known concerning its function in endometrial cancer. Our study was conducted to evaluate the expression and therapeutic potential of CDK9 in endometrial cancer. CDK9 expression was determined by immunohistochemistry in endometrial cancer tissues constructed with paired primary, metastatic, and recurrent tumor tissues from 32 endometrial cancer patients. Small interfering RNA (siRNA) and inhibitors of CDK9 were used to evaluate the effect of CDK9 inhibition on the anti-apoptotic activity and proliferation in endometrial cancer cells. Colony formation assay and wound-healing assays were adopted to assess clonal formation and migratory capacity. The results of the immunohistochemistry demonstrated that CDK9 was highly expressed in the human endometrial cancer cell lines; moreover, it was elevated in metastatic and recurrent endometrial tumor tissue compared when compared with that in patient-matched primary endometrial tumor tissue. Knockdown of CDK9 with siRNA and inhibition of CDK9 activity with the inhibitor suppressed cell proliferation and promoted apoptosis in endometrial cancer. In conclusion, our results provide evidence that CDK9 may be a potential prognostic biomarker and a promising therapeutic target for the treatment of endometrial cancer in the future.

Development of a PROTAC-Based Targeting Strategy Provides a Mechanistically Unique Mode of Anti-Cytomegalovirus Activity

“…Treating cells with 10 µM ganciclovir (GCV) showed no effect in resolving HCMV inhibition of migration compared with infected untreated cells ( p = 0.999). Treating cells with 0.5 µM THAL-SNS032 almost completely abolished trophoblast migration consistent with the importance of CDK9 in cell migration [ 36 , 37 , 38 ]. Immunofluorescence analysis showed that there was no significant difference in levels of the HCMV immediate early protein expression between the treatment groups 24 h p.i.…”

Targeting CDK9 for Anti-Cancer Therapeutics

“…CDK9 expression had been implicated in the prognosis and resistance to anti-cancer therapeutics in a large number of cancer types like those of breast, lung, prostate, endometrium, apart from melanoma, osteosarcoma, myeloid leukemia, soft tissue sarcomas etc. [ 1 , 88 , 89 , 90 , 91 , 92 ]. We will briefly explain some of these cancer entities here.…”

“…Concentration dependent knock-down of CDK9 expression and dose-dependent inhibition of CDK9 activity by LDC000067 led to correspondingly significant reductions in cell viability and MCL-1 expression while BAX expression and PARP cleavage were enhanced. Additionally, 14 days of treatment with increasing concentrations of LDC000067 resulted in significant reductions of clonogenicity and 2D migration of endometrial cancer cell lines [ 90 ].…”

“…LDC000067 ( Table 2 ) was synthesized by Albert et al as an ATP competitive inhibitor with in vitro IC 50 of 44 nM (CDK9), 2.4 µM (CDK2) and >10 µM (CDK6/7), as against 5.2, 15, 305 and 103 nM, respectively, for Flavopiridol [ 138 ]. As has been mentioned in the previous sections, due to the high specificity of LDC000067 against CDK9, it has proved to be a valuable tool in pre-clinical studies against multiple and diverse cancer entities [ 88 , 90 , 94 , 116 ]. However, no clinical trials of LDC000067 were ever undertaken ( Table 2 ).…”

Targeting CDK9 for the Treatment of Glioblastoma

“…The idea that transcriptional programs are highly dysregulated in cancers and that cancers become over-dependent on certain factors that control gene expression has led to increased efforts to inhibit transcriptional CDKs, such as CDK9 [ 21 ]. Preclinical studies in several cancer types, including osteosarcoma, synovial sarcoma, endometrial cancer, and leukemia, have focused on targeting CDK9 due to its role in controlling transcription of super-enhancer driven oncogenes such as MYC and anti-apoptotic proteins such as myeloid-cell leukemia 1 (MCL-1), which maintain cancer cell survival [ 22 , 23 , 24 , 25 , 26 ]. Clinically, it has been observed that CDK9 is overexpressed in many cancer types, such as pancreatic cancer, osteosarcoma, synovial sarcoma, and endometrial cancer [ 23 , 24 , 25 , 27 , 28 ], and that a high CDK9 expression correlates with poor patient prognosis [ 23 , 24 , 25 , 27 ].…”