Androgen Receptor and Poly(ADP-ribose) Glycohydrolase Inhibition Increases Efficiency of Androgen Ablation in Prostate Cancer Cells

Abstract

There is mounting evidence of androgen receptor signaling inducing genome instability and changing DNA repair capacity in prostate cancer cells. Expression of genes associated with base excision repair (BER) is increased with prostate cancer progression and correlates with poor prognosis. Poly(ADPribose) polymerase (pARp) and poly(ADp-ribose) glycohydrolase (pARG) are key enzymes in BeR that elongate and degrade pAR polymers on target proteins. While pARp inhibitors have been tested in clinical trials and are a promising therapy for prostate cancer patients with TMPRSS2-ERG fusions and mutations in DNA repair genes, PARG inhibitors have not been evaluated. We show that PARG is a direct androgen receptor (AR) target gene. AR is recruited to the pARG locus and induces pARG expression. Androgen ablation combined with PARG inhibition synergistically reduces BER capacity in independently derived LNCaP and LAPC4 prostate cancer cell lines. A combination of PARG inhibition with androgen ablation or with the DNA damaging drug, temozolomide, significantly reduces cellular proliferation and increases DNA damage. PARG inhibition alters AR transcriptional output without changing AR protein levels. thus, AR and pARG are engaged in reciprocal regulation suggesting that the success of androgen ablation therapy can be enhanced by PARG inhibition in prostate cancer patients. Late stage prostate cancers are treated with radiation and other cytotoxic therapies. It was observed that androgen ablation sensitizes prostate tumors to radiation and chemotherapy in prostate cancer patients 1-3. Prostate tumors with high androgen receptor (AR) transcriptional output have increased expression of DNA repair genes in general, and base excision repair (BER) associated proteins in particular 4,5. Conversely, AR upregulates pathways in prostate cancer that increase genomic instability, such as the TMPRSS2-ERG gene fusion, which is present in a significant part of advanced prostate cancers 5,6. Importantly, inhibition of poly(ADP-ribose) polymerase 1 (PARP1) significantly increases levels of DNA damage in such tumors 7 and is currently being tested in clinical trials in metastatic castration resistant prostate cancer (CRPC) with somatic or germline mutations in DNA repair genes. The PARP inhibitors rucaparib (NCT02952534, NCT03533946 and NCT03413995) and olaparib (NCT02316197, NCT03012321, NCT03787680, NCT03432897 and others) have been tested in clinical trials and were granted breakthrough designation by the U.S. Food and Drug Administration (FDA) for metastatic CRPC. Poly(ADP-ribose) glycohydrolase (PARG) and PARP1 are key enzymes required for DNA repair and maintenance of genomic stability. Poly ADP-ribose (PAR) is a heterogeneous branched polymer of ADP-ribose that is attached to proteins in response to various stimuli by a dynamic process called PARylation. PARylation regulates DNA damage detection and repair as PAR acts as a loading platform to recruit a variety of DNA repair factors, in a non-covalent fashion, to the DNA lesions. Multiple ...

Base excision repair and its implications to cancer therapy

“…For example, PARG activity can increase the expression of androgen receptor by removing inhibitory poly(ADP-ribosyl)ation from the transcriptional coactivator KDM4D. PARGi, PDD00017272, enhanced the effect of androgen ablation on prostate cancer cell lines, by further reducing androgen receptor signalling in addition to increased cytotoxic breaks arising from the inhibition of BER [ 100 ]. The development of other PARGi (e.g.…”

Identification of PANoptosis-Based Prognostic Signature for Predicting Efficacy of Immunotherapy and Chemotherapy in Hepatocellular Carcinoma

“…High activity of BER was one of the main reasons for chemoresistance [ 34 ]. Recently, targeting BER enzymes had achieved a good effect in clinical trials [ 35 , 36 ]. Thus, chemotherapy in combination with BER enzyme inhibitors might be a better option for cancer with strong chemotherapy resistance.…”

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“…This observed impact on key DSB repair genes raises interest in the potential enhancement of these effects through synthetic lethality approaches, with mounting evidence supporting the combination of inhibiting both the AR and the PARP pathway (26)(27)(28)(29). The potential combination of AR suppression and DNA damage response (DDR) inhibitors to increase clinical efficacy is not only limited to PARP inhibition.…”