{"doi":"10.1002/ctd2.345","title":"Tracking down metabolic vulnerabilities in <i>CDK12</i>‐mutant prostate cancer","abstract":"CDK12 is among the most frequently mutated cyclin-dependent kinases (CDKs) in various cancers, including prostate, ovarian, breast, esophageal, bladder, and colon cancers.1 Specifically, biallelic aberrations of CDK12 occur in 3%–7% of metastatic castration-resistant prostate cancer (mCRPC) cases and correlate with poor prognosis.1 One of the most well-studied functions of CDK12 is its orchestration of transcription initiation and elongation through cyclin K-dependent Ser2 phosphorylation of RNA polymerase II,2 and therefore CDK12 is important in regulating the expression of long genes or genes with high exon numbers, especially DNA damage response (DDR)-related genes such as BRCA1, ATR, FANCI, and FANCD21.3 As a result, CDK12-deficient cancers are commonly characterized by focal tandem duplications (FTDs) and various features of genome instability.4, 5 Because FTDs often generate a large amount of neoantigens, it has been suggested that CDK12-deficient tumours may be more sensitive to immunotherapy.5 However, studies of immune checkpoint blockade therapy have shown only limited effects in mCRPC patients harbouring CDK12 mutations.6 Likewise, despite the observed sensitization of CDK12-deficient ovarian cancer cells to PARP inhibitors (PARPi) due to impaired DDR functionality,7 clinical trials of PARPi have produced unsatisfactory results in prostate cancer patients with CDK12 mutations.6 Therefore, there is an urgent need to identify exploitable vulnerabilities in CDK12-deficient prostate cancer. In a recent study, Zhang et al. investigated the impact of CDK12 deficiency on cell metabolism and tumour progression in prostate cancer.8 By analyzing public datasets, they confirmed an association between CDK12 deficiency and poor prognosis in mCRPC, while noting higher levels of CDK12 mutations in Chinese patients (15.4%–27.2%) than in the global populations (4.7%). To further delineate how CDK12 deficiency promotes mCRPC, they generated CDK12-knockout prostate cancer cell lines using CRISPR-Cas9 technology and conducted metabolomic and transcriptomic analyses. The resulting data showed that CDK12 deficiency reprogrammed energy metabolisms in prostate cancer cells; specifically, CDK12 knockout cells exhibited higher levels of metabolites related to glycolysis, glutaminolysis, and the tricarboxylic acid cycle, but lower levels of metabolites related to β-oxidation. Further, the associated RNA-seq data showed enrichment of mitochondrial electron transport chain (ETC) and oxidative phosphorylation-related pathways in CDK12-deficient prostate cancers, suggesting that CDK12 deficiency promotes mCRPC progression by enhancing mitochondrial ETC-dependent energy production (Figure 1). The Zhang team also found that CDK12 knockout cell lines consistently showed significantly increased adenosine triphosphate (ATP) production compared to controls. ETC activity has previously been associated with the generation of reactive oxygen species, which induce various types of cell death including ferroptosis. Ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, was recently identified as an emerging therapeutic target in a range of cancers including prostate cancer.9 Zhang et al. tested whether ferroptosis could be a potential therapeutic vulnerability in the context of CDK12 deficiency. Surprisingly, they found that despite depletion of intracellular antioxidant substances such as cysteine and glutathione due to ETC upregulation, CDK12 knockout cells were more resistant to ferroptosis inducers, including RSL3 and erastin, than control cells. Mechanistically, they found that dysregulation of lipid metabolism-related genes and alterations in metabolites involved in the phospholipid biosynthesis pathway that were typical of CDK12-deficient prostate cancer cells reduced their susceptibility to ferroptosis. As they probed further, they identified ACSL4 among all lipid metabolism-related genes as the most downregulated g","journal":"Clinical and Translational Discovery","year":2024,"id":501239,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9634,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1019819,"name":"Mu‐En Wang","orcid":"0000-0002-5953-3499","position":1,"is_corresponding":false},{"id":23869,"name":"Ming Chen","orcid":"0000-0002-3470-1062","position":2,"is_corresponding":false},{"id":1350772,"name":"Wei-Hsiang Tu","orcid":null,"position":0,"is_corresponding":true}],"reference_count":12,"raw_metadata":null,"created_at":"2026-07-19T02:10:12.068207Z","pmid":"39183936","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}