Exploiting the DNA Damage Response for Prostate Cancer Therapy

Abstract

Prostate cancers that progress despite androgen deprivation develop into castration-resistant prostate cancer, a fatal disease with few treatment options. In this review, we discuss the current understanding of prostate cancer subtypes and alterations in the DNA damage response (DDR) that can predispose to the development of prostate cancer and affect its progression. We identify barriers to conventional treatments, such as radiotherapy, and discuss the development of new therapies, many of which target the DDR or take advantage of recurring genetic alterations in the DDR. We place this in the context of advances in understanding the genetic variation and immune landscape of CRPC that could help guide their use in future treatment strategies. Finally, we discuss several new and emerging agents that may advance the treatment of lethal disease, highlighting selected clinical trials.

Keywords: ATM; ATR; DNA damage response; DNA-PK; PARP; androgen; hypoxia; immunotherapy; prostate cancer; radiopharmaceutical therapy; radiotherapy.

Figure 1

(A) Schematic of the AR gene and AR and selected AR-V protein domains. Protein domains are described in the text and color coded to the exon schematic. Selected agents that target protein domains are indicated in red (see text for further details) [18,19,20,21]. AR-VAR7 arises due to the splicing to cryptic exon 3 (CE3) and ARV567es from the deletion of exons 5–7; cell lines that express each of the selected genes endogenously are listed [6]. (B) Progression of PCa and identified CRPC subtypes are depicted [22]. Key transcription factors (TFs) and some commonly used cell lines representing the subtypes are shown.

Figure 2

(A) Schematic of the DNA damage response. DNA lesions are sensed, activating signal transduction networks that trigger cell cycle checkpoints and DNA repair, as well as cell fate decisions like apoptosis and senescence. (B) Example of synthetic lethality. Targeting GENE2 is tolerated by normal cells but is toxic to cancer cells due to a dependency on the function of GENE1 that is mutated (indicated by star) in the cancer cell. (C) Schematic of the major sources of DNA damage (indicated by star) in PCa. Endogenous DSBs arise due to topoisomerase activity during transcription and through replication stress: the slowing or stalling of replication forks and accumulation of ssDNA. Genotoxic treatments used in therapy, including RT, topoisomerase 2 inhibitors (etoposide, mitoxantrone) and platinum agents, such as cisplatin and carboplatin, cause base lesions, DNA interstrand strand crosslinks (ICL), SSBs, and DSBs through distinct mechanisms. (D) Summaries of selected DNA lesions (orange) and repair pathways (blue). Major factors (black) and steps (red) of double-strand break repair (DSBR), single-strand break repair (SSBR), base excision repair (BER) and mismatch repair (MMR) are depicted. Connections between DSBR pathways, classical non-homologous end joining (cNHEJ), homologous recombination (HR), and polymerase theta mediated end joining (TMEJ) are shown. Nucleotide excision repair, ICL repair, and DNA–protein crosslink repair details are omitted for brevity. See text and references for additional information and perspectives [41,42,43,44,45,46,47,48,49,50,51].

Figure 3

(A) Oncoprint of selected DDR genes in the recurrent chromosome 6q deletion in samples from two PCa cohorts; SU2C/PCF Dream Team (mCRPC) and MSK/DFCI (Prostate Adenocarcinoma) [83,123,124,125,143]. Selected DDR genes that are typically lost in the 6q deletion and their relative locations are highlighted (see text for details). PARP sensitizers BRCA2 and RNASEH2B are shown for comparison, along with common driver gene TP53. Note that the 6q locus deletions show mutual exclusivity with TP53 (cbioportal.org). Patient samples without alterations in the selected genes are omitted for brevity. (B) Sensitivity (NormZ-score) to selected agents in RPE1-hTERT-Cas9-TP53-/- cells in CRISPR screens [127]. PARPi = Olaparib and ATRi = AZD6738.

Figure 4

Summary of current and emerging therapies to treat CRPC. Selected genetic alterations (green italics) that sensitize to particular therapies (black bold) are shown. See text for full details.