Targeting XRCC1 (X-ray repair cross-complementing gene 1) deficiency in tumors for personalized cancer therapy.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1014-1014
Author(s):  
Srinivasan Madhusudan ◽  
Tarek M. A. Abdel-Fatah ◽  
Rebeka Sultana ◽  
Rachel Abbotts ◽  
Claire Hawkes ◽  
...  
Keyword(s):  
Synthetic Lethality ◽  
Excision Repair ◽  
Human Cancer ◽  
Chinese Hamster ◽  
Fold Increase ◽  
Strand Break ◽  
Poor Survival ◽  
Single Strand Break ◽  
Risk Of Death ◽  
Break Repair

1014 Background: XRCC1 is essential for DNA base excision repair, single strand break repair and nucleotide excision repair. XRCC1 deficiency promotes genomic instability and may increase cancer risk. Methods: We evaluated XRCC1 immunohistochemically in early stage breast (n=2046), ovarian (n=157), gastric (n=140), colorectal (n=250) and pancreaticobiliary cancers (n=240). Pre-clinically, we evaluated a panel of XRCC1 deficient and proficient Chinese hamster ovary and human cancer cell lines. Double strand break repair (DSB) inhibitors targeting ATM (KU55933), DNA-PKcs (NU7441) and ATR (NU6027) were evaluated for synthetic lethality and cisplatin alone or in combination with DSB inhibitors for chemopotentiation. Results: In breast cancer,XRCC1 loss (16%) was associated with higher grade (p<0.0001), loss of hormone receptors (p<0.0001), presence of triple negative (p<0.0001) and basal like phenotypes (p=0.001). Loss of XRCC1 was associated with a 2-fold increase in risk of death and metastasis (p<0.0001) and independently with poor outcome (p<0.0001). In ovarian cancer, XRCC1 was positive in 44% of tumour and was significantly associated with higher stage (p=0.001), clear/endometroid type (p=0.015) and sub-optimal debulking (p=0.004). XRCC1 positive tumours were more resistant to platinum chemotherapy (p=0.0001). XRCC1 positivity conferred a 2 fold increase of risk of death (p=0.002) and independently associated with poor survival (p=0.002). In gastric cancers, XRCC1 was positive in 37% of tumours. This was significantly associated with high stage disease (p=0.001) and poor survival (p=0.001). Pre-clinically, KU55933, NU7441 and NU6027 were synthetically lethal in XRCC1 deficient compared to proficient cells as evidenced by DSB accumulation, G2/M cell cycle arrest and apoptosis. XRCC1 deficient cells were hypersensitive to cisplatin which was enhanced by DSB repair inhibitors compared to in proficient cells. Conclusions: This is the largest study to confirm the clinical significance of XRCC1 expression in solid tumours. XRCC1 deficiency in human tumours may be suitable for synthetic lethality application and exploited for cisplatin chemotherapy potentiation.

scholarly journals PARP Inhibitors and Myeloid Neoplasms: A Double-Edged Sword

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6385
Author(s):  
Clifford M. Csizmar ◽  
Antoine N. Saliba ◽  
Elizabeth M. Swisher ◽  
Scott H. Kaufmann
Keyword(s):  
De Novo ◽  
Excision Repair ◽  
Alkylating Agents ◽  
Strand Break ◽  
Parp Inhibitors ◽  
Molecular Characteristics ◽  
Single Strand Break ◽  
Myeloid Neoplasms ◽  
Long Term Treatment ◽  
Break Repair

Despite recent discoveries and therapeutic advances in aggressive myeloid neoplasms, there remains a pressing need for improved therapies. For instance, in acute myeloid leukemia (AML), while most patients achieve a complete remission with conventional chemotherapy or the combination of a hypomethylating agent and venetoclax, de novo or acquired drug resistance often presents an insurmountable challenge, especially in older patients. Poly(ADP-ribose) polymerase (PARP) enzymes, PARP1 and PARP2, are involved in detecting DNA damage and repairing it through multiple pathways, including base excision repair, single-strand break repair, and double-strand break repair. In the context of AML, PARP inhibitors (PARPi) could potentially exploit the frequently dysfunctional DNA repair pathways that, similar to deficiencies in homologous recombination in BRCA-mutant disease, set the stage for cell killing. PARPi appear to be especially effective in AML with certain gene rearrangements and molecular characteristics (RUNX1-RUNX1T1 and PML-RARA fusions, FLT3- and IDH1-mutated). In addition, PARPi can enhance the efficacy of other agents, particularly alkylating agents, TOP1 poisons, and hypomethylating agents, that induce lesions ordinarily repaired via PARP1-dependent mechanisms. Conversely, emerging reports suggest that long-term treatment with PARPi for solid tumors is associated with an increased incidence of myelodysplastic syndrome (MDS) and AML. Here, we (i) review the pre-clinical and clinical data on the role of PARPi, specifically olaparib, talazoparib, and veliparib, in aggressive myeloid neoplasms and (ii) discuss the reported risk of MDS/AML with PARPi, especially as the indications for PARPi use expand to include patients with potentially curable cancer.

scholarly journals Race specific differences in DNA damage repair dysregulation in breast cancer and association with outcome

2020 ◽  
Author(s):  
Aloran Mazumder ◽  
Athena Jimenez ◽  
Rachel E Ellsworth ◽  
Stephen J Freedland ◽  
Sophia George ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Strand Break ◽  
Normal Breast ◽  
Breast Cancer Patients ◽  
Poor Survival ◽  
Single Strand Break ◽  
Multiple Datasets ◽  
Single Strand Break Repair ◽  
Damage Repair ◽  
Break Repair

AbstractIMPORTANCEAfrican American (AA) breast cancer patients have worse outcomes than Caucasian Americans (CAs). DNA damage repair (DDR) genes drive poor outcome in CA estrogen receptor (ER)+ breast cancer patients. Whether DDR genes similarly impact survival in AAs is unknown. Identifying AA-specific patterns of DDR dysregulation could change how we tailor predictive/prognostic biomarkers.OBJECTIVETo characterize DDR dysregulation in ER+ AA patient tumors and test associations with clinical outcome.DESIGN SETTINGS AND PARTICIPANTSThree independent tumor, and two normal breast datasets were analyzed. Tumor datasets: (1) GSE78958 (2) GSE18229 (3) The Cancer Genome Atlas (TCGA). Normal datasets: (4) GSE43973 (5) GSE50939.MAIN OUTCOME AND MEASURESUp/down-regulation of 104 DDR genes was assessed in AA samples vs CAs. Survival associations were assessed for genes dysregulated in multiple datasets.RESULTSOverall, RNA levels of single strand break repair (SSBR) genes were downregulated in AA tumors and double strand break repair (DSBR) genes were upregulated compared to CAs. While SSBR downregulation was mainly detected in tumors, DSBR upregulation was detectable in both tumor and normal breast AA samples. Seven specific DDR genes identified as dysregulated in AAs vs CAs in multiple datasets associated with poor survival. A subset of tumors with simultaneous dysregulation of homologous recombination and single strand break repair genes was enriched in AAs and had associated consistently with poor survival.CONCLUSION AND RELEVANCEOverall, these results constitute the first systematic analysis of differences in DDR regulation in AA ER+ tumors and normal tissue vs CAs. We identify a profile of DDR dysregulation enriched in AA patients, which associates with poor outcome. These results suggest a distinct molecular mechanism of DDR regulation in AAs that lays the groundwork for refining biomarker profiles by race and improving precision medicine for underserved populations.

scholarly journals XRCC1 deficient triple negative breast cancers are sensitive to ATR, ATM and Wee1 inhibitor either alone or in combination with olaparib

2020 ◽  
Vol 12 ◽  
pp. 175883592097420
Author(s):  
Reem Ali ◽  
Adel Alblihy ◽  
Michael S. Toss ◽  
Mashael Algethami ◽  
Rabab Al Sunni ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Repair ◽  
Triple Negative ◽  
Germ Line ◽  
Synthetic Lethality ◽  
Excision Repair ◽  
Parp Inhibitor ◽  
Strand Break ◽  
Breast Cancers ◽  
Single Strand Break

Background: PARP inhibitor (PARPi) monotherapy is a new strategy in BRCA germ-line deficient triple negative breast cancer (TNBC). However, not all patients respond, and the development of resistance limits the use of PARPi monotherapy. Therefore, the development of alternative synthetic lethality strategy, including in sporadic TNBC, is a priority. XRCC1, a key player in base excision repair, single strand break repair, nucleotide excision repair and alternative non-homologous end joining, interacts with PARP1 and coordinates DNA repair. ATR, ATM and Wee1 have essential roles in DNA repair and cell cycle regulation. Methods: Highly selective inhibitors of ATR (AZD6738), ATM (AZ31) and Wee1 (AZD1775) either alone or in combination with olaparib were tested for synthetic lethality in XRCC1 deficient TNBC or HeLa cells. Clinicopathological significance of ATR, ATM or Wee1 co-expression in XRCC1 proficient or deficient tumours was evaluated in a large cohort of 1650 human breast cancers. Results: ATR (AZD6738), ATM (AZ31) or Wee1 (AZD1775) monotherapy was selectively toxic in XRCC1 deficient cells. Selective synergistic toxicity was evident when olaparib was combined with AZD6738, AZ31 or AZD1775. The most potent synergistic interaction was evident with the AZD6738 and olaparib combination therapy. In clinical cohorts, ATR, ATM or Wee1 overexpression in XRCC1 deficient breast cancer was associated with poor outcomes. Conclusion: XRCC1 stratified DNA repair targeted combinatorial approach is feasible and warrants further clinical evaluation in breast cancer.

scholarly journals Activated STAT3 Is a Novel Regulator of the XRCC1 Promoter and Selectively Increases XRCC1 Protein Levels in Triple Negative Breast Cancer

2021 ◽  
Vol 22 (11) ◽  
pp. 5475
Author(s):  
Griffin Wright ◽  
Manoj Sonavane ◽  
Natalie R. Gassman
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Excision Repair ◽  
Strand Break ◽  
Xrcc1 Gene ◽  
Single Strand Break ◽  
Expression Levels ◽  
Constitutive Activation ◽  
Gene And Protein Expression

Base Excision Repair (BER) addresses base lesions and abasic sites induced by exogenous and endogenous stressors. X-ray cross complementing group 1 (XRCC1) functions as a scaffold protein in BER and single-strand break repair (SSBR), facilitating and coordinating repair through its interaction with a host of critical repair proteins. Alterations of XRCC1 protein and gene expression levels are observed in many cancers, including colorectal, ovarian, and breast cancer. While increases in the expression level of XRCC1 are reported, the transcription factors responsible for this up-regulation are not known. In this study, we identify the signal transducer and activator of transcription 3 (STAT3) as a novel regulator of XRCC1 through chromatin immunoprecipitation. Activation of STAT3 through phosphorylation at Y705 by cytokine (IL-6) signaling increases the expression of XRCC1 and the occupancy of STAT3 within the XRCC1 promoter. In triple negative breast cancer, the constitutive activation of STAT3 upregulates XRCC1 gene and protein expression levels. Increased expression of XRCC1 is associated with aggressiveness and resistance to DNA damaging chemotherapeutics. Thus, we propose that activated STAT3 regulates XRCC1 under stress and growth conditions, but constitutive activation in cancers results in dysregulation of XRCC1 and subsequently BER and SSBR.

End-damage-specific proteins facilitate recruitment or stability of X-ray cross-complementing protein 1 at the sites of DNA single-strand break repair

FEBS Journal ◽  
2005 ◽  
Vol 272 (22) ◽  
pp. 5753-5763 ◽  
Author(s):  
Jason L. Parsons ◽  
Irina I. Dianova ◽  
Emma Boswell ◽  
Michael Weinfeld ◽  
Grigory L. Dianov
Keyword(s):  
Strand Break ◽  
Single Strand ◽  
Single Strand Break ◽  
X Ray ◽  
Single Strand Break Repair ◽  
Specific Proteins ◽  
Break Repair
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