Changes in DNA Damage Response Markers with Treatment in Advanced Ovarian Cancer

Kubelac, Paul; Genestie, Catherine; Auguste, Aurélie; Mesnage, Soizick; Formal, Audrey Le; Pautier, Patricia; Gouy, Sébastien; Morice, Philippe; Bentivegna, Enrica; Maulard, Amandine; Adam, Julien; Achimaș-Cădariu, Patriciu; Leary, Alexandra

doi:10.3390/cancers12030707

Cited by 15 publications

(9 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Both platinum chemotherapy and PARPi are genotoxic agents, which exploit defects in DDR pathways to affect cancer cell death [19]. Alterations in DDR (including upregulation or downregulation of key effectors) can drive sensitivity or resistance to these agents (Table 2) [20].…”

Section: Alterations In Dna Damage Repair Can Drive Treatment Resistancementioning

confidence: 99%

Overcoming Platinum and PARP-Inhibitor Resistance in Ovarian Cancer

McMullen

Karakasis

Madariaga

et al. 2020

Cancers

109

View full text Add to dashboard Cite

Platinum chemotherapy remains the cornerstone of treatment for epithelial ovarian cancer (OC) and Poly (ADP-ribose) polymerase inhibitors (PARPi) now have an established role as maintenance therapy. The mechanisms of action of these agents is, in many ways, complementary, and crucially reliant on the intracellular DNA Damage Repair (DDR) response. Here, we review mechanisms of primary and acquired resistance to treatment with platinum and PARPi, examining the interplay between both classes of agents. A key resistance mechanism appears to be the restoration of the Homologous Recombination (HR) repair pathway, through BRCA reversion mutations and epigenetic upregulation of BRCA1. Alterations in non-homologous end-joint (NHEJ) repair, replication fork protection, upregulation of cellular drug efflux pumps, reduction in PARP1 activity and alterations to the tumour microenvironment have also been described. These resistance mechanisms reveal molecular vulnerabilities, which may be targeted to re-sensitise OC to platinum or PARPi treatment. Promising therapeutic strategies include ATR inhibition, epigenetic re-sensitisation through DNMT inhibition, cell cycle checkpoint inhibition, combination with anti-angiogenic therapy, BET inhibition and G-quadruplex stabilisation. Translational studies to elucidate mechanisms of treatment resistance should be incorporated into future clinical trials, as understanding these biologic mechanisms is crucial to developing new and effective therapeutic approaches in advanced OC.

show abstract

Section: Alterations In Dna Damage Repair Can Drive Treatment Resistancementioning

confidence: 99%

Overcoming Platinum and PARP-Inhibitor Resistance in Ovarian Cancer

McMullen

Karakasis

Madariaga

et al. 2020

Cancers

109

View full text Add to dashboard Cite

show abstract

“…The models generated here compare favourably with other methods of classification that have been proposed for high grade serous cancer including DNA [21,39] and RNA [40] based models. Moreover the functional approach to these assays is justified by the incremental improvement in prediction seen with these assays compared to recent studies using an IHC approach [41], and similar results in glioblastoma multiforme [42] with a panel including the host-cell reactivation system used here [25].…”

Section: Discussionmentioning

confidence: 91%

The heterogeneity of the DNA damage response landscape determines patient outcomes in ovarian cancer

Walker

Faraahi

Price

et al. 2021

Preprint

View full text Add to dashboard Cite

Defective DNA damage response (DDR) pathways allow cancer cells to accrue genomic aberrations and evade normal cellular growth checkpoints. Defective DDR also determines response to chemotherapy. However, the interaction and overlap between the two double strand repair pathways and the three single strand repair pathways is complex, and has remained poorly understood. Here we show that, in ovarian cancer, a disease hallmarked by chromosomal instability, explant cultures show a range of DDR abrogation patterns. Defective homologous recombination (HR) and non-homologous end joining (NHEJ) are near mutually exclusive with HR deficient (HRD) cells showing increased abrogation of the single strand repair pathways compared to NHEJ defective cells. When combined with global markers of DNA damage, including mitochondrial membrane functionality and reactive oxygen species burden, the pattern of DDR abrogation allows the construction of DDR signatures which are predictive of both ex vivo cytotoxicity, and more importantly, patient outcome.

show abstract

“…The response of cells to DNA damage is an important determinant of tumor development. Chemoradiotherapy usually induces DSBs to exert cytotoxicity, so alterations in DDR can drive sensitivity or resistance to these agents [ 44 ]. Inhibition of DNA damage repair proteins can not only be used as a sensitizer combined with DNA damaging agent but also as a single antitumor drug [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Lamin-A interacting protein Hsp90 is required for DNA damage repair and chemoresistance of ovarian cancer cells

Wang

Chen

et al. 2021

Cell Death Dis

View full text Add to dashboard Cite

Ovarian cancer is the most malignant gynecologic cancer. Previous studies found that lamin-A was associated with DNA damage repair proteins but the underlying mechanism remains unclear. We speculate that this may be related to its interacting proteins, such as Hsp90. The aim of this study is to investigate the effects of Hsp90 on DNA damage repair and chemoresistance of ovarian cancer cells. In our research, co-immunoprecipitation (co-IP) and mass spectrometry (MS) were used to identify proteins interacting with lamin-A and the interaction domain. Next, the relationship between lamin-A and Hsp90 was explored by Western blotting (WB) and immunofluorescence staining. Then, effect of Hsp90 inhibition on DNA damage repair was assessed through detecting Rad50 and Ku80 by WB. Furthermore, to test the roles of 17-AAG on cell chemosensitivity, CCK-8 and colony formation assay were carried out. Meanwhile, IC50 of cells were calculated, followed by immunofluorescence to detect DNA damage. At last, the mouse xenograft model was used in determining the capacity of 17-AAG and DDP to suppress tumor growth and metastatic potential. The results showed that lamin-A could interact with Hsp90 via the domain of lamin-A1-430. Besides, the distribution of Hsp90 could be affected by lamin-A. After lamin-A knockdown, Hsp90 decreased in the cytoplasm and increased in the nucleus, suggesting that the interaction between lamin-A and Hsp90 may be related to the nucleocytoplasmic transport of Hsp90. Moreover, inhibition of Hsp90 led to an obvious decrease in the expression of DSBs (DNA double-strand break) repair proteins, as well as cell proliferation ability upon DDP treatment and IC50 of DDP, causing more serious DNA damage. In addition, the combination of 17-AAG and DDP restrained the growth of ovarian cancer efficiently in vivo and prolonged the survival time of tumor-bearing mice.

show abstract

Changes in DNA Damage Response Markers with Treatment in Advanced Ovarian Cancer

Cited by 15 publications

References 46 publications

Overcoming Platinum and PARP-Inhibitor Resistance in Ovarian Cancer

Overcoming Platinum and PARP-Inhibitor Resistance in Ovarian Cancer

The heterogeneity of the DNA damage response landscape determines patient outcomes in ovarian cancer

Lamin-A interacting protein Hsp90 is required for DNA damage repair and chemoresistance of ovarian cancer cells

Contact Info

Product

Resources

About