Double trouble for prostate cancer: synergistic action of AR blockade and PARPi in non-HRR mutated patients.
HRR genes
PARP inhibition (PARPi)
androgen receptor signaling inhibitor
prostate cancer
synergistic effect (combined treatment)
Journal
Frontiers in oncology
ISSN: 2234-943X
Titre abrégé: Front Oncol
Pays: Switzerland
ID NLM: 101568867
Informations de publication
Date de publication:
2023
2023
Historique:
received:
23
07
2023
accepted:
05
09
2023
medline:
9
10
2023
pubmed:
9
10
2023
entrez:
9
10
2023
Statut:
epublish
Résumé
Prostate cancer (PCa) is the most common cancer in men worldwide. Despite better and more intensive treatment options in earlier disease stages, a large subset of patients still progress to metastatic castration-resistant PCa (mCRPC). Recently, poly-(ADP-ribose)-polymerase (PARP)-inhibitors have been introduced in this setting. The TALAPRO-2 and PROpel trials both showed a marked benefit of PARPi in combination with an androgen receptor signaling inhibitor (ARSI), compared with an ARSI alone in both the homologous recombination repair (HRR)-mutated, as well as in the HRR-non-mutated subgroup. In this review, we present a comprehensive overview of how maximal AR-blockade via an ARSI in combination with a PARPi has a synergistic effect at the molecular level, leading to synthetic lethality in both HRR-mutated and HRR-non-mutated PCa patients. PARP2 is known to be a cofactor of the AR complex, needed for decompacting the chromatin and start of transcription of AR target genes (including HRR genes). The inhibition of PARP thus reinforces the effect of an ARSI. The deep androgen deprivation caused by combining androgen deprivation therapy (ADT) with an ARSI, induces an HRR-like deficient state, often referred to as "BRCA-ness". Further, PARPi will prevent the repair of single-strand DNA breaks, leading to the accumulation of DNA double-strand breaks (DSBs). Due to the induced HRR-deficient state, DSBs cannot be repaired, leading to apoptosis.
Identifiants
pubmed: 37810962
doi: 10.3389/fonc.2023.1265812
pmc: PMC10551452
doi:
Types de publication
Journal Article
Review
Langues
eng
Pagination
1265812Informations de copyright
Copyright © 2023 Giesen, Baekelandt, Devlies, Devos, Dumez, Everaerts, Claessens and Joniau.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
Références
Eur Urol. 2021 Feb;79(2):263-282
pubmed: 33039206
CA Cancer J Clin. 2021 May;71(3):209-249
pubmed: 33538338
Mol Cancer Ther. 2015 Aug;14(8):1896-906
pubmed: 26026052
Drug Des Devel Ther. 2015 Jun 29;9:3325-39
pubmed: 26170619
Eur Urol. 2014 Jul;66(1):32-9
pubmed: 24054872
Clin Cancer Res. 2020 Apr 15;26(8):2047-2064
pubmed: 31796516
Sci Signal. 2014 May 20;7(326):ra47
pubmed: 24847116
Cancer Discov. 2013 Nov;3(11):1222-4
pubmed: 24203954
Signal Transduct Target Ther. 2020 Oct 7;5(1):227
pubmed: 33028824
Lancet. 2020 Apr 11;395(10231):1208-1216
pubmed: 32209449
J Clin Oncol. 2018 Apr 1;36(10):991-999
pubmed: 29261439
Front Oncol. 2021 Jul 21;11:700543
pubmed: 34367984
Nat Commun. 2017 Aug 29;8(1):374
pubmed: 28851861
Biomedicines. 2022 Jun 15;10(6):
pubmed: 35740437
Oncogene. 2015 May 28;34(22):2815-22
pubmed: 25132269
Exp Ther Med. 2022 May;23(5):351
pubmed: 35493432
Cancer Cell. 2011 May 17;19(5):664-78
pubmed: 21575865
Trends Pharmacol Sci. 2019 Feb;40(2):128-141
pubmed: 30612715
Science. 2017 Jan 6;355(6320):78-83
pubmed: 28059767
Sci Signal. 2017 May 23;10(480):
pubmed: 28536297
Cancer Discov. 2018 Apr;8(4):444-457
pubmed: 29367197
IUBMB Life. 2017 Dec;69(12):929-937
pubmed: 29171189
BJU Int. 2016 Feb;117(2):215-25
pubmed: 25818596
DNA Repair (Amst). 2018 Nov;71:177-182
pubmed: 30177435
Cancers (Basel). 2021 Oct 28;13(21):
pubmed: 34771580
Trends Cell Biol. 2019 Sep;29(9):740-751
pubmed: 31362850
Lancet Oncol. 2018 Jul;19(7):975-986
pubmed: 29880291
Endocr Relat Cancer. 2014 Oct;21(5):R395-407
pubmed: 25096064
EMBO Rep. 2021 Dec 6;22(12):e52764
pubmed: 34661369
Cancer Discov. 2013 Nov;3(11):1245-53
pubmed: 24027196
J Clin Oncol. 2023 Jun 20;41(18):3339-3351
pubmed: 36952634
Trends Cancer. 2020 Nov;6(11):974-984
pubmed: 32517958
Lancet. 2023 Jul 22;402(10398):291-303
pubmed: 37285865
Front Oncol. 2019 Aug 28;9:801
pubmed: 31555580
Am J Pathol. 2004 Jan;164(1):217-27
pubmed: 14695335
Cancer Discov. 2013 Nov;3(11):1254-71
pubmed: 24027197
Proc Natl Acad Sci U S A. 2019 Jul 16;116(29):14573-14582
pubmed: 31266892
JCO Precis Oncol. 2017 Jul;2017:
pubmed: 28825054
Nat Rev Cancer. 2016 Feb;16(2):110-20
pubmed: 26775620
BJU Int. 2023 Jul 17;:
pubmed: 37461140
Eur Urol Oncol. 2023 Aug 11;:
pubmed: 37574390
Cancer Discov. 2012 Dec;2(12):1134-49
pubmed: 22993403
Cancer Res. 2017 Feb 15;77(4):982-995
pubmed: 27923835
Front Oncol. 2018 May 24;8:180
pubmed: 29911070
Nat Rev Urol. 2014 Dec;11(12):712-6
pubmed: 25224448
Nat Rev Mol Cell Biol. 2011 Jun;12(6):385-92
pubmed: 21527953
Environ Mol Mutagen. 2017 Jun;58(5):235-263
pubmed: 28485537
BMC Med. 2015 Aug 13;13:188
pubmed: 26268938
Prostate. 2022 Aug;82 Suppl 1:S45-S59
pubmed: 35657156
Clin Cancer Res. 2009 Jan 15;15(2):677-83
pubmed: 19147774
Eur Urol. 2015 Aug;68(2):186-93
pubmed: 25454609
Cancers (Basel). 2021 Feb 22;13(4):
pubmed: 33671614
Cancer Biol Ther. 2009 Apr;8(8):665-70
pubmed: 19287209
J Pathol. 2012 Jul;227(3):336-45
pubmed: 22431170
Proc Natl Acad Sci U S A. 2011 Feb 22;108(8):3406-11
pubmed: 21300883
Nat Rev Mol Cell Biol. 2019 Nov;20(11):698-714
pubmed: 31263220