Targeting the DNA Damage Response in CDK12-Mutant Prostate Cancer

项目总结

PROJECT SUMMARY Prostate cancer is the second most common cause of cancer death among men in the United States. While early-stage prostate cancers often respond to hormonal therapy, a subset progresses to an incurable state known as castration-resistant prostate cancer (CRPC), which is resistant to standard hormonal therapies. New therapeutic agents for molecularly-defined subsets of CRPC are urgently needed. Mutations in cyclin dependent kinase 12 (CDK12), a transcription-associated protein kinase, are found in 1-2% of localized prostate cancer and 6-8% of CRPC. The identification of therapies that are effective in this clinically aggressive molecular subtype of mCRPC remains a pressing and unmet clinical need. Intriguingly, mutations in CDK12 are associated with distinctive tumor genomic features, including a genome-wide pattern of tandem duplications, the amplification of oncogenes, the utilization of cryptic internal polyadenylation sites, and an increased frequency of gene fusions. Several of these features have been associated in other contexts with increased DNA replication stress (RS), which arises from aberrant origin firing or when DNA replication forks encounter DNA damage or stalled transcriptional complexes. Under normal conditions, the RS response is activated by signaling through the ATR/Chk1 kinase pathway, leading to coordinated DNA repair events that promote replication fork re-start. Under conditions of elevated RS, which occur in some cancers, there is increased dependence on ATR/Chk1 signaling for survival. Indeed, several ATR inhibitors (ATRi) are now in clinical development and have shown promising activity in Phase I/II trials in unselected populations. The hypothesis underlying this project is that CDK12-mutant prostate cancer is associated with increased RS, thereby resulting in a sensitization to ATRi. Through the following aims, we explore the mechanism-driven application of ATRi and poly(ADP-ribose) polymerase inhibitors (PARPi) in CDK12-mutant prostate cancer. First, in Aim 1, we use cell line models and immunostaining of prostate cancer tissues to determine whether CDK12 loss is associated with the increased expression of RS markers. Next, in Aim 2, we test ATRi as monotherapy or in combination with PARPi in both in vitro and in vivo models of CDK12-mutant prostate cancer. Together, this exploratory project aims to lay the framework for the design of biomarker-selected clinical trials of ATRi monotherapy and/or combination therapy for CDK12-altered mCRPC and to influence clinical practice paradigms for this aggressive subset of mCRPC that is poorly responsive to the current standard therapies.