Characterizing CDK12-Mutated Prostate Cancers

Abstract

CDK12 aberrations have been reported as a biomarker of response to immunotherapy for metastatic castration-resistant prostate cancer (mCRPC). Herein, we characterize CDK12mutated mCRPC, presenting clinical, genomic, and tumor-infiltrating lymphocyte data.

New Prognostic Biomarkers in Metastatic Castration-Resistant Prostate Cancer

“…CDK12 is reportedly involved in regulating expression of several HR genes [ 77 ]; somatic defects in CDK12 are associated with a genome-wide focal tandem duplication (FTD) signature [ 78 ]. Multiple retrospective studies have reported a worse survival for CK12 mutant mCRPC, which are also characterized by a high Gleason score (>8) and a tumor immune infiltrate, potentially immunosuppressive, comprised of CD4+FOXP3- cells [ 79 ]. The FTD phenotype has also been correlated with increased neo-antigen burden in those tumors, positioning CDK12 among the putative biomarkers of response to novel immunotherapies in mCRPC [ 74 ].…”

Immune Checkpoints, Inhibitors and Radionuclides in Prostate Cancer: Promising Combinatorial Therapy Approach

“…The loss of biallaelic CDK12 is another important phenomenon and hallmark of MMR pathway deficiency in selected HRPC cases. This is usually characterised by increased gene fusions, which serve as neoantigens and promote intratumoral T cell infiltration that can potentially be targeted with pembrolizumab [63,89]. It is only 7% of HRPC patients that exhibit this genomic aberration, which means a one-size-fits-all approach that is currently being used must be reviewed and changed to specialised treatment.…”

A comprehensive mechanistic basis of prostate cancer advancement & its personalized implementation-bridging the gap: present state and future prospect

“…Towards identification of patient specific optimal sequences for these future therapeutic measures, there is a growing requirement for identification of suitable biomarkers to guide effective treatment selection and characterization of treatment responses [24]. Recently, a number of genomic aberrations have been proposed as predictive biomarker for evaluation of treatment response profiles like cyclin-dependent kinase 12 (CDK12) and DNA damage repairs (DDR) associated breast cancer gene 1 (BRCA1) as well as ataxia telangiectasia mutated (ATM) in CRPC patients [142,143]. It has been suggested that the biallelic loss of CDK12 are prevalent in around 5% of metastatic CRPCs and intrinsically associated with immunosuppression through massive infiltration of CD4 + FOXP3 − T lymphocytes in prostate TME, which strongly urges for the interventions with immunotherapeutic approaches [142].…”

“…Recently, a number of genomic aberrations have been proposed as predictive biomarker for evaluation of treatment response profiles like cyclin-dependent kinase 12 (CDK12) and DNA damage repairs (DDR) associated breast cancer gene 1 (BRCA1) as well as ataxia telangiectasia mutated (ATM) in CRPC patients [142,143]. It has been suggested that the biallelic loss of CDK12 are prevalent in around 5% of metastatic CRPCs and intrinsically associated with immunosuppression through massive infiltration of CD4 + FOXP3 − T lymphocytes in prostate TME, which strongly urges for the interventions with immunotherapeutic approaches [142]. On the other hand, it has been reported that nearly 11.8% of metastatic CRPCs have germ line alterations in DNA damage response associated mediators like BRAC1, BRCA2 and ATM, which are typically associated with the significant levels of response towards poly (adenosine diphosphate ribose) polymerase (PARP) inhibitor Olaparib [114,143].…”

“…On the other hand, it has been reported that nearly 11.8% of metastatic CRPCs have germ line alterations in DNA damage response associated mediators like BRAC1, BRCA2 and ATM, which are typically associated with the significant levels of response towards poly (adenosine diphosphate ribose) polymerase (PARP) inhibitor Olaparib [114,143]. Based on recent TOPARP-A and TOPARP-B clinical trials among metastatic CRPC patients, PARP inhibitor Olaparib has been recommended as a personalized therapeutic agents in advanced prostate cancer for corresponding DDR defects accompanied by a marked enhancement in patients progression free survival (PFS) [20,114,142,143]. Further strategic development of this kind of molecular stratification based treatment approaches for metastatic CRPCs will be of great demand in very near future with much accuracies.…”