Inactivation of CDK12 Delineates a Distinct Immunogenic Class of Advanced Prostate Cancer

Abstract

SUMMARY Using integrative genomic analysis of 360 metastatic castration-resistant prostate cancer (mCRPC) samples, we identified a novel subtype of prostate cancer typified by biallelic loss of CDK12 that is mutually exclusive with tumors driven by DNA repair deficiency, ETS fusions, and SPOP mutations. CDK12 loss is enriched in mCRPC relative to clinically-localized disease and characterized by focal tandem duplications (FTDs) that lead to increased gene fusions and marked differential gene expression. FTDs associated with CDK12 loss result in highly recurrent gains at loci of genes involved in the cell cycle and DNA replication. CDK12-mutant cases are baseline diploid and do not exhibit DNA mutational signatures linked to defects in homologous recombination. CDK12-mutant cases are associated with elevated neoantigen burden ensuing from fusion-induced chimeric open reading frames and increased tumor T cell infiltration/clonal expansion. CDK12 inactivation thereby defines a distinct class of mCRPC that may benefit from immune checkpoint immunotherapy.

CDK12 controls G1/S progression by regulating RNAPII processivity at core DNA replication genes

“…Recent findings show that many cancers with disrupted CDK12 catalytic activity have a unique, CDK12-inactivation-specific genome instability phenotype: tandem duplications [29][30][31][32][33]. There are several possible scenarios for their genesis; nevertheless, we favor the concept that they arise due to disrupted expression of both core DNA replication and HR genes upon inhibition of CDK12.…”

“…They consist of large (up to 2-10 Mb in size) tandem duplications, which are completely different from other genome alteration patterns, including those observed in BRCA1-and other HR-inactivated tumors. Furthermore, they are characterized by an increased sensitivity to cisplatin and thus represent potential biomarker for treatment response [29][30][31][32][33]. Although inactivation of CDK12 kinase activity clearly leads to HR defects and sensitivity to PARP inhibitors in cells [21,[34][35][36][37], the discovery of the CDK12 inactivation-specific tandem duplication phenotype indicated a distinct function of CDK12 in maintenance of genome stability.…”

“…Although inactivation of CDK12 kinase activity clearly leads to HR defects and sensitivity to PARP inhibitors in cells [21,[34][35][36][37], the discovery of the CDK12 inactivation-specific tandem duplication phenotype indicated a distinct function of CDK12 in maintenance of genome stability. The size and distribution of the tandem duplications suggested that DNA replication stress-mediated defect(s) are a possible driving force for their formation [30,31].…”

Hyperprogression and Immune Checkpoint Inhibitors: Hype or Progress?

“…There are various genomic aberrations that correlate with immunotherapy response, including (but not limited to) (A) mismatch repair gene defects that result in high microsatellite instability (MSI), (B) high tumor mutational burden (TMB), (C) PBRM1 and CDK12 mutations, and (D) PD‐L1 amplification . Other biomarkers include high PD‐L1 protein expression, gut microbiome, and POLE , ATM (TMB‐mediated), ATR (TMB‐mediated), and CDK12 mutations, which have been shown to predict response to immunotherapy . Of interest in this regard, pembrolizumab was granted the first tissue‐agnostic approval by the FDA in patients with mismatch repair gene‐altered/MSI‐high solid tumors of any type, based on response rates of ∼40% .…”

Extreme responses to immune checkpoint blockade following bipolar androgen therapy and enzalutamide in patients with metastatic castration resistant prostate cancer

“…However, a subset of patients with mCRPC do derive significant benefit from immune checkpoint inhibitors 5 . These immunologically responsive tumors may harbor homologous recombination (HR), DNA repair gene mutations, 6 inactivating CDK12 mutations, 7,8 or mismatch repair deficiency 9,10 …”