Tracking down metabolic vulnerabilities in CDK12‐mutant prostate cancer

Abstract

CDK12 is among the most frequently mutated cyclindependent 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 Wei-Ling Tu andMu-En Wang contributed equally.