SEI1 induces genomic instability by inhibiting DNA damage response in ovarian cancer

2017 ◽  
Vol 385 ◽  
pp. 271-279 ◽  
Author(s):  
Jia You ◽  
Jia Liu ◽  
Yantao Bao ◽  
Liqun Wang ◽  
Yang Yu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Genomic Instability ◽  
Dna Damage Response ◽  
Damage Response

Emerging roles of lamins and DNA damage repair mechanisms in ovarian cancer

2020 ◽  
Vol 48 (5) ◽  
pp. 2317-2333
Author(s):  
Duhita Sengupta ◽  
Asima Mukhopadhyay ◽  
Kaushik Sengupta
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Genomic Instability ◽  
Dna Damage Response ◽  
Dna Damage Repair ◽  
Serous Carcinoma ◽  
Intermediate Filament Proteins ◽  
Damage Repair ◽  
Wide Range ◽  
Damage Response

Lamins are type V intermediate filament proteins which are ubiquitously present in all metazoan cells providing a platform for binding of chromatin and related proteins, thereby serving a wide range of nuclear functions including DNA damage repair. Altered expression of lamins in different subtypes of cancer is evident from researches worldwide. But whether cancer is a consequence of this change or this change is a consequence of cancer is a matter of future investigation. However changes in the expression levels of lamins is reported to have direct or indirect association with cancer progression or have regulatory roles in common neoplastic symptoms like higher nuclear deformability, increased genomic instability and reduced susceptibility to DNA damaging agents. It has already been proved that loss of A type lamin positively regulates cathepsin L, eventually leading to degradation of several DNA damage repair proteins, hence impairing DNA damage repair pathways and increasing genomic instability. It is established in ovarian cancer, that the extent of alteration in nuclear morphology can determine the degree of genetic changes and thus can be utilized to detect low to high form of serous carcinoma. In this review, we have focused on ovarian cancer which is largely caused by genomic alterations in the DNA damage response pathways utilizing proteins like RAD51, BRCA1, 53BP1 which are regulated by lamins. We have elucidated the current understanding of lamin expression in ovarian cancer and its implications in the regulation of DNA damage response pathways that ultimately result in telomere deformation and genomic instability.

scholarly journals Genomic, Transcriptomic, and Functional Alterations in DNA Damage Response Pathways as Putative Biomarkers of Chemotherapy Response in Ovarian Cancer

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1420
Author(s):  
Sweta Sharma Saha ◽  
Lucy Gentles ◽  
Alice Bradbury ◽  
Dominik Brecht ◽  
Rebecca Robinson ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Personalised Medicine ◽  
Primary Cultures ◽  
The Cancer Genome Atlas ◽  
Chemotherapy Response ◽  
Chemotherapy Drugs ◽  
Ovarian Cancers ◽  
Damage Response

Defective DNA damage response (DDR) pathways are enabling characteristics of cancers that not only can be exploited to specifically target cancer cells but also can predict chemotherapy response. Defective Homologous Recombination Repair (HRR) function, e.g., due to BRCA1/2 loss, is a determinant of response to platinum agents and PARP inhibitors in ovarian cancers. Most chemotherapies function by either inducing DNA damage or impacting on its repair but are generally used in the clinic unselectively. The significance of HRR and other DDR pathways in determining response to several other chemotherapy drugs is not well understood. In this study, the genomic, transcriptomic and functional analysis of DDR pathways in a panel of 14 ovarian cancer cell lines identified that defects in DDR pathways could determine response to several chemotherapy drugs. Carboplatin, rucaparib, and topotecan sensitivity were associated with functional loss of HRR (validated in 10 patient-derived primary cultures) and mismatch repair. Two DDR gene expression clusters correlating with treatment response were identified, with PARP10 identified as a novel marker of platinum response, which was confirmed in The Cancer Genome Atlas (TCGA) ovarian cancer cohort. Reduced non-homologous end-joining function correlated with increased sensitivity to doxorubicin, while cells with high intrinsic oxidative stress showed sensitivity to gemcitabine. In this era of personalised medicine, molecular/functional characterisation of DDR pathways could guide chemotherapy choices in the clinic allowing specific targeting of ovarian cancers.

scholarly journals 900 Depleting non-canonical, cell-intrinsic PD-L1 signals induces synthetic lethality to small molecule DNA damage response inhibitors in an immune independent and dependent manner

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A944-A944
Author(s):  
Anand Kornepati ◽  
Clare Murray ◽  
Barbara Avalos ◽  
Cody Rogers ◽  
Kavya Ramkumar ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Dna Repair ◽  
Cell Lines ◽  
Dna Damage Response ◽  
Small Molecule ◽  
Treatment Resistance ◽  
Programmed Death ◽  
Damage Response ◽  
Response Biomarker

BackgroundTumor surface-expressed programmed death-ligand 1 (PD-L1) suppresses immunity when it engages programmed death-1 (PD-1) on anti-tumor immune cells in canonical PD-L1/PD-1.1 Non-canonical, tumour-intrinsic PD-L1 signals can mediate treatment resistance2–6 but mechanisms remain incompletely understood. Targeting non-canonical, cell-intrinsic PD-L1 signals, especially modulation of the DNA damage response (DDR), remains largely untapped.MethodsWe made PD-L1 knockout (PD-L1 KO) murine transplantable and human cell lines representing melanoma, bladder, and breast histologies. We used biochemical, genetic, and cell-biology techniques for mechanistic insights into tumor-intrinsic PD-L1 control of specific DDR and DNA repair pathways. We generated a novel inducible melanoma GEMM lacking PD-L1 only in melanocytes to corroborate DDR alterations observed in PD-L1 KO of established tumors.ResultsGenetic tumor PD-L1 depletion destabilized Chk2 and impaired ATM/Chk2, but not ATR/Chk1 DDR. PD-L1KO increased DNA damage (γH2AX) and impaired homologous recombination DNA repair (p-RPA32, BRCA1, RAD51 nuclear foci) and function (DR-GFP reporter). PD-L1 KO cells were significantly more sensitive versus controls to DDR inhibitors (DDRi) against ATR, Chk1, and PARP but not ATM in multiple human and mouse tumor models in vitro and in vivo in NSG mice. PD-1 independent, intracellular, not surface PD-L1 stabilized Chk2 protein with minimal Chek2 mRNA effect. Mechanistically, PD-L1 could directly complex with Chk2, protecting it from PIRH2-mediated polyubiquitination. PD-L1 N-terminal domains Ig-V and Ig-C but not the PD-L1 C-terminal tail co-IP’d with Chk2 and restored Chk1 inhibitor (Chk1i) treatment resistance. Tumor PD-L1 expression correlated with Chk1i sensitivity in 44 primary human small cell lung cancer cell lines, implicating tumor-intrinsic PD-L1 as a DDRi response biomarker. In WT mice, genetic PD-L1 depletion but not surface PD-L1 blockade with αPD-L1, sensitized immunotherapy-resistant, BRCA1-WT 4T1 tumors to PARP inhibitor (PARPi). PARPi effects were reduced on PD-L1 KO tumors in RAG2KO mice indicating immune-dependent DDRi efficacy. Tumor PD-L1 depletion, likely due to impaired DDR, enhanced PARPi induced tumor-intrinsic STING activation (e.g., p-TBK1, CCL5) suggesting potential to augment immunotherapies.ConclusionsWe challenge the prevailing surface PD-L1 paradigm and establish a novel mechanism for cell-intrinsic PD-L1 control of the DDR and gene product expression. We identify therapeutic vulnerabilities from tumor PD-L1 depletion utilizing small molecule DDRi currently being tested in clinical trials. Data could explain αPD-L1/DDRi treatment resistance. Intracellular PD-L1 could be a pharmacologically targetable treatment target and/or response biomarker for selective DDRi alone plus other immunotherapies.ReferencesTopalian SL, Taube JM, Anders RA, Pardoll DM. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer 16:275–287, doi:10.1038/nrc.2016.36 (2016).Clark CA, et al. Tumor-intrinsic PD-L1 signals regulate cell growth, pathogenesis and autophagy in ovarian cancer and melanoma. Canres 0258.2016 (2016).Gupta HB et al. Tumor cell-intrinsic PD-L1 promotes tumor-initiating cell generation and functions in melanoma and ovarian cancer. 1, 16030 (2016).Zhu H, et al. BET bromodomain inhibition promotes anti-tumor immunity by suppressing PD-L1 expression. Cell Rep 16:2829–2837, doi:10.1016/j.celrep.2016.08.032 (2016)Wu B, et al. Adipose PD-L1 modulates PD-1/PD-L1 checkpoint blockade immunotherapy efficacy in breast cancer. Oncoimmunology 7:e1500107, doi:10.1080/2162402X.2018.1500107 (2018)Liang J, et al. Verteporfin inhibits PD-L1 through autophagy and the STAT1-IRF1-TRIM28 signaling axis, exerting antitumor efficacy. Cancer Immunol Res 8:952–965, doi:10.1158/2326-6066.CIR-19-0159 (2020)

scholarly journals miR-211 facilitates platinum chemosensitivity by blocking the DNA damage response (DDR) in ovarian cancer

2019 ◽  
Vol 10 (7) ◽  
Author(s):  
Tianzhen Wang ◽  
Dapeng Hao ◽  
Shucai Yang ◽  
Jianhui Ma ◽  
Weiwei Yang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Damage Response

Abstract 3641: The predictive and prognostic roles of DNA damage response genes in epithelial ovarian cancer

2012 ◽  
Author(s):  
Nicolette G. Alkema ◽  
Marieke Everts ◽  
Ate G.J. van der Zee ◽  
Klaske A. ten Hoor ◽  
Harry Hollema ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Epithelial Ovarian Cancer ◽  
Dna Damage Response ◽  
Damage Response

scholarly journals Tribbles 2 mediates cisplatin sensitivity and DNA damage response in epithelial ovarian cancer

2017 ◽  
Vol 141 (8) ◽  
pp. 1600-1614 ◽  
Author(s):  
Daniel Kritsch ◽  
Franziska Hoffmann ◽  
Daniel Steinbach ◽  
Lars Jansen ◽  
Stella Mary Photini ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Epithelial Ovarian Cancer ◽  
Dna Damage Response ◽  
Damage Response ◽  
Cisplatin Sensitivity
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