CDK12

The encoding gene of CDK12 is located on autochromosome 17 and can encode 1490 amino acids. The encoding protein has a molecular weight of 164 kDa. The main structure of CDK12 includes proline-rich motifs (PRM) and arginine/ Serine rich motifs (PRM). RS) and the kinase domain, which has catalytic functions. The kinase domain is located in the central part of the protein and consists of 300 amino acids responsible for substrate phosphorylation (PMID: 11683387, PMID: 34316683). CDK12 is known to have three main functions: (1) CDK12 phosphorylates RNA polymerase PoL ⅱ to promote transcription elongation; (2) CDK12 interacts with RNA processing factors to regulate splicing; (3) Mediate the phosphorylation of RNA polymerase ⅱ with transcription and the processing of mRNA 3 'end, and regulate the polyadenylation of introns (PMID: 32570740, PMID: 30487607). CDK12 can regulate gene transcription, including DNA damage repair genes. When the function of CDK12 protein is inactivated, the expression defect of DNA damage repair genes will be caused, which will quickly cause genomic instability and lead to the occurrence of tumors. The analysis of TCGA data showed that the CDK12 gene had specific mutation frequency in all cancers, among which esophageal cancer, endometrial cancer, and bladder cancer had higher mutation frequency, which ranged from 10% to 15%. CDK12 mutations have also been widespread in gastric, colorectal, pancreatic, and high-grade serous ovarian cancers (PMID: 30104286).

Treatment of CDK12 mutation-induced tumors based on platinum/PARP inhibitor drugs is a standard clinical chemotherapy method. Its mechanism of action is that platinum molecules combine with non-complementary paired bases of DNA molecules, resulting in conformational changes and affecting DNA replication and transcription. These damaged sites can be repaired by nucleotide excision (NER). Studies have shown that tumor cells are significantly more sensitive to platinum-based chemotherapy when DNA damage repairs gene functional defects. The loss of CDK12 function can lead to the silencing of DNA damage repair gene expression, forming the state of "DNA damage repair gene defect", which may increase the sensitivity of tumor cells to platinum chemotherapy (PMID: 29025359, PMID: 27880910). PARP1 is an enzyme that repairs DNA single-strand breaks (SSB) through base excisions, when the PARP enzyme binds to PARP inhibitor (PARPi), the single strand damage cannot be repaired in time, resulting in double-strand breaks (DSB). In defects of homologous recombination repair genes (commonly BRCA1, BRCA2), DNA damage cannot be repaired, and cells die. CDK12 function loss leads to DNA damage repair gene defects, resulting in tumor cells being sensitive to PARPi (PMID: 28302823, PMID: 27880910). Moreover, CDK inhibitors have been studied and applied to cancer treatment. Dinaciclib is a multi-specific CDK inhibitor that exhibits potent antiproliferative effects on various cancers. Dinaciclib inhibits phosphorylation of Ser2 of RNAP II CTD and downregulates HR DNA repair genes and can reverse the resistance of PARP inhibitor, converting tumor growth inhibition to durable regression (PMID: 29992508, PMID: 20663931).THZ1 is a CDK7 inhibitor and has therapeutic effects on both breast and lung cancer. It has been demonstrated that high concentrations of THZ1 can also be used as an inhibitor of CDK12 (PMID: 25043025). THZ531 is a novel CDK12/13 inhibitor, it has potential for treatment of TNBC through the downregulation of core DNA damage response (DDR) genes and upregulation of genes involved in cell apoptosis (PMID: 31519701). SR-4835 is another CDK12/13 inhibitor that acts synergistically with PARP inhibitors to inhibit cell proliferation. One clinical trial in Phase I adopts dinaciclib and veliparib (PARP-1 inhibitor ABT-888) for treatment in patients with advanced solid tumors (PMID: 31668947, NCT01434316).