Role and therapeutic potential of CDK12 in human cancers

Cyclin K dependent regulation of Aurora B affects apoptosis and proliferation by induction of mitotic catastrophe in prostate cancer

“…However, the results from this study are in accordance with previous studies, which show that CycK is highly expressed in testicular tumours compared to noncancerous cells and co‐localizes with Ki67, a proliferation marker . Interestingly, the binding partners of CycK, CDK12 and CDK13, have been reported to be highly overexpressed genetically in several tumour entities . Furthermore, low levels of CDK12 in ovarian cancer patients, who receive platinum therapy, show improved survival compared to patients with high CDK12 levels …”

“…10 Interestingly, the binding partners of CycK, CDK12 and CDK13, have been reported to be highly overexpressed genetically in several tumour entities. 46,47 Furthermore, low levels of CDK12 in ovarian cancer patients, who receive platinum therapy, show improved survival compared to patients with high CDK12 levels. 48 These observations lead to the question why patients with low CycK expression benefit more from an antitumor therapy.…”

The impact of DNA damage response gene polymorphisms on therapeutic outcomes in late stage ovarian cancer

“…The selected genes code for proteins involved in key pathways of cellular response to different DNA damaging agents, including platinum263233, that represents the gold standard in ovarian adjuvant therapy. Cisplatin (DDP) is an alkylating agent, whose cytotoxic effects are mainly related to its ability to cause DNA damage, that is repaired by the coordinated action of homologous recombination (HR), nucleotide excision repair (NER) and fanconi anemia (FA)34.…”

“…While polymorphisms of genes involved in specific DNA repair pathways have been studied in correlation with platinum-efficacy in many different patients cohort (i.e lung and ovarian patients)1837383940, less information is available in upstream sensor DDR proteins. This is why we focused on the role of polymorphisms in genes involved in the initial activation of the cellular response to a given damage ( ATM/Chk2 and ATR/Chk1 axis) and on CDK12 , recently recognized as an important regulator of DDR in ovarian cancer33. None of the ATM , ATR , Chk1 and Chk2 polymorphisms was found to significantly affect OS nor PFS in ourcohort of advanced stage ovarian cancer patients treated with adjuvant chemotherapy, while genotype G/G of CDK12 polymorphism (rs1054488) predicted worse OS and PFS than the genotype A/A-A/G in univariate analysis.…”

“…genes involved in DNA repair4849. It has been shown to be mutated in different tumortypes33 and the Cancer Genome Atlas Research Network (TGCA) revealed it to be mutated in 3% of the 316 high grade ovarian sequenced samples, with a prevalence similar to the one observedfor BRCA-1 and BRCA-2 (3.5 and 3.2% respectively)50. More importantly, these mutations have been shown to have functional consequences disabling the enzyme catalytic activity and hampering the ability of CDK12 to promote target gene expression51.…”