Silencing of MBD1 reverses pancreatic cancer therapy resistance through inhibition of DNA damage repair

AbstractGenomic instability is the hallmark of various cancers with the increasing accumulation of DNA damage. The application of radiotherapy and chemotherapy in cancer treatment is typically based on this property of cancers. However, the adverse effects including normal tissues injury are also accompanied by the radiotherapy and chemotherapy. Targeted cancer therapy has the potential to suppress cancer cells’ DNA damage response through tailoring therapy to cancer patients lacking specific DNA damage response functions. Obviously, understanding the broader role of DNA damage repair in cancers has became a basic and attractive strategy for targeted cancer therapy, in particular, raising novel hypothesis or theory in this field on the basis of previous scientists’ findings would be important for future promising druggable emerging targets. In this review, we first illustrate the timeline steps for the understanding the roles of DNA damage repair in the promotion of cancer and cancer therapy developed, then we summarize the mechanisms regarding DNA damage repair associated with targeted cancer therapy, highlighting the specific proteins behind targeting DNA damage repair that initiate functioning abnormally duo to extrinsic harm by environmental DNA damage factors, also, the DNA damage baseline drift leads to the harmful intrinsic targeted cancer therapy. In addition, clinical therapeutic drugs for DNA damage and repair including therapeutic effects, as well as the strategy and scheme of relative clinical trials were intensive discussed. Based on this background, we suggest two hypotheses, namely “environmental gear selection” to describe DNA damage repair pathway evolution, and “DNA damage baseline drift”, which may play a magnified role in mediating repair during cancer treatment. This two new hypothesis would shed new light on targeted cancer therapy, provide a much better or more comprehensive holistic view and also promote the development of new research direction and new overcoming strategies for patients.

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DNA Damage Repair and Response Proteins as Targets for Cancer Therapy

Current Medicinal Chemistry ◽

10.2174/092986708783497328 ◽

2008 ◽

Vol 15 (4) ◽

pp. 360-367 ◽

Cited By ~ 51

Author(s):

Howard Lieberman

Keyword(s):

Dna Damage ◽

Cancer Therapy ◽

Dna Damage Repair ◽

Damage Repair

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Development and application of compact and on-chip electron linear accelerators for dynamic tracking cancer therapy and DNA damage/repair analysis

IOP Conference Series Materials Science and Engineering ◽

10.1088/1757-899x/79/1/012015 ◽

2015 ◽

Vol 79 ◽

pp. 012015 ◽

Cited By ~ 1

Author(s):

M Uesaka ◽

K Demachi ◽

T Fujiwara ◽

K Dobashi ◽

H Fujisawa ◽

...

Keyword(s):

Dna Damage ◽

Cancer Therapy ◽

Dna Damage Repair ◽

Linear Accelerators ◽

Dynamic Tracking ◽

Damage Repair ◽

On Chip

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Deeper Insight in Metastatic Cancer progression;Epithelial-to-Mesenchymal Transition and Genomic Instability: implications on treatment resistance

Current Molecular Medicine ◽

10.2174/1566524021666210202114844 ◽

2021 ◽

Vol 21 ◽

Author(s):

Kenneth Omabe ◽

Sandra Uduituma ◽

David Igwe ◽

Maxwell Omabe

Keyword(s):

Dna Damage ◽

Cancer Treatment ◽

Epithelial To Mesenchymal Transition ◽

Dna Damage Repair ◽

Treatment Resistance ◽

Therapy Resistance ◽

Cellular Reprogramming ◽

Repair System ◽

Mesenchymal Transition ◽

Damage Repair

: Therapy resistance remains the major obstacle to successful cancer treatment. Epithelial-to- mesenchymal transition [EMT], a cellular reprogramming process involved in embryogenesis and organ development and regulated by a number of transcriptional factors [EMT-TFs] such as ZEB1/2, is recognized for its role in tumor progression and metastasis. Recently, a growing body of evidence has implicated EMT in cancer therapy resistance but the actual mechanism that underlie this finding has remained elusive. For example, whether it is, the EMT states in itself or the EMT-TFs that modulates chemo or radio-resistance in cancer is still contentious. Here, we summarise the molecular mechanisms of EMT program and chemotherapeutic resistance in cancer with specific reference to DNA damage response [DDR]. We provide an insight into the molecular interplay that exist between EMT program and DNA repair machinery in cancer and how this interaction influences therapeutic response. We review conflicting studies linking EMT and drug resistance via the DNA damage repair axis. We draw scientific evidence demonstrating how several molecular signalling, including EMT-TFs work in operational harmony to induce EMT and confer stemness properties on the EMT-susceptible cells. We highlight the role of enhanced DNA damage repair system associated with EMT-derived stem cell-like states in promoting therapy resistance and suggest a multi-targeting modality in combating cancer treatment resistance.

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DNA damage, repair and the improvement of cancer therapy – A tribute to the life and research of Barbara Tudek

Mutation Research/Genetic Toxicology and Environmental Mutagenesis ◽

10.1016/j.mrgentox.2020.503160 ◽

2020 ◽

Vol 852 ◽

pp. 503160

Author(s):

Agnieszka Tudek ◽

Jolanta Czerwińska ◽

Konrad Kosicki ◽

Daria Zdżalik-Bielecka ◽

Somayeh Shahmoradi Ghahe ◽

...

Keyword(s):

Dna Damage ◽

Cancer Therapy ◽

Dna Damage Repair ◽

Damage Repair

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Retrospective review of outcomes in patients with DNA-damage repair related pancreatic cancer

Hereditary Cancer in Clinical Practice ◽

10.1186/s13053-020-00148-9 ◽

2020 ◽

Vol 18 (1) ◽

Author(s):

Sarah K. Macklin-Mantia ◽

Stephanie L. Hines ◽

Pashtoon M. Kasi

Keyword(s):

Pancreatic Cancer ◽

Dna Damage ◽

Retrospective Review ◽

Dna Damage Repair ◽

Damage Repair

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Radiosensitization of metformin in pancreatic cancer cells via abrogating the G2 checkpoint and inhibiting DNA damage repair

Cancer Letters ◽

10.1016/j.canlet.2015.08.015 ◽

2015 ◽

Vol 369 (1) ◽

pp. 192-201 ◽

Cited By ~ 24

Author(s):

Zheng Wang ◽

Song-Tao Lai ◽

Ning-Yi Ma ◽

Yun Deng ◽

Yong Liu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Dna Damage ◽

Cancer Cells ◽

Dna Damage Repair ◽

G2 Checkpoint ◽

Pancreatic Cancer Cells ◽

Damage Repair

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Retrospective analysis of patients using olaparib (O) in pancreatic cancer (PC).

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.389 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 389-389

Author(s):

Erkut Hasan Borazanci ◽

Carol Guarnieri ◽

Susan Haag ◽

Ronald Lee Korn ◽

Courtney Edwards Snyder ◽

...

Keyword(s):

Pancreatic Cancer ◽

Dna Damage ◽

Dna Repair ◽

Retrospective Analysis ◽

Pearson Correlation ◽

Brca2 Mutation ◽

Dna Damage Repair ◽

Parp Inhibitors ◽

Damage Repair ◽

Repair Deficiency

389 Background: Molecular analysis has revealed four subtypes of PC giving clinicians further insight into treating this deadly disease. One subtype that was elucidated termed “unstable” is significant for the presence of DNA damage repair deficiency and can be targeted therapeutically. One such therapy, O, from the drug class poly ADP ribose polymerase (PARP) inhibitors, has already been FDA approved for individuals with BRCA mutated ovarian cancers. We performed a retrospective analysis on patients with PC treated at a single institution who have DNA damage repair deficiency mutations and have been treated with O. Methods: A chart review identified pancreatic cancer patients with DNA repair pathway mutations who were treated with O. The primary objective examined ORR in patients with PC with DNA repair mutations receiving O. Secondary objectives included tolerability, overall survival (OS), CA 19-9 change, and changes in quantitative textural analysis (QTA) on CT. Results: 11 individuals were identified, 5 carriers of a pathogenic germline (g) BRCA2 mutation, 1 carrier of a pathogenic g ATM mutation, 1 carrier of a pathogenic g BRCA1 mutation. Variants of uncertain significance (VUS) included 1 g ATM mutation, 1 g PALB2 mutation, 1 somatic (s) C11orf30 mutation, and 1 s BRCA2 mutation. Median age at diagnosis was 59, with 4 M and 7 F. No patients met criteria for familial PC and 7 had a family history consistent for breast and ovarian cancer syndrome. All individuals had metastatic PC and had progressed on at least 1 line of systemic therapy. ORR was 18%. Median time of therapy on O was 5 months (mo) (Range 1.4 to 29.567 mo) with 5 of the individuals still undergoing treatment at the time of analysis. Mean OS was 12.35 mo, 9 of the 11 individuals still alive. QTA of baseline CTs from subjects with liver (8/11) and pancreatic tumors (7/11) revealed a strong association between lesion texture and OS (Pearson correlation coefficient (PCC): hepatic mets = 0.952, p = 0.0003) and time on O (PCC: panc lesions = 0.889, p = 0.006). Conclusions: In individuals with metastatic PC with mutations involved in DNA repair, O may provide clinical benefit. QTA of individual tumors may allow for additional information that predicts outcomes to PARP inhibitors in this population.

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Identification of Genetic Determinants of Pancreatic Cancer Immune Phenotypes by Integrative Genome-scale Analysis

10.21203/rs.3.rs-212097/v1 ◽

2021 ◽

Author(s):

Yuhang Ling ◽

Jiaqi Xu ◽

Xuedong Wang ◽

Jie Song ◽

Qiuhui Qian ◽

...

Keyword(s):

Pancreatic Cancer ◽

Immune Response ◽

Dna Damage ◽

Immune System ◽

Immune Cell ◽

Dna Damage Repair ◽

Cell Interactions ◽

Tumor Microenvironments ◽

Damage Repair ◽

Immune Phenotypes

Abstract Background Pancreatic cancer (PC) is a malignant neoplasm of the digestive tract that is highly malignant and difficult to diagnose at an early stage with high postoperative mortality and low cure rates. Cancer immunotherapy is innovating the clinical treatment of several cancers, but has a limited role in PC. The incomplete understanding of immune response hinders the development of gene therapy. To fill this gap, it is very necessary to classify the immunogenic subtypes of PC to understand the relationship between tumor microenvironments and clinical pathological characteristics, DNA damage repair and tumor immune response.Methods We extracted copy number change, somatic mutation and expression data from tumor genome map (TCGA). Using RNA sequencing data, we defined three different immunophenotypes and elucidated how immune cell interactions in immune subtypes vary with the background of the immune system. Further correlation analysis between DNA damage repair (DDR) related genes expression and immune response was conducted to explore the effects of DDR expression on antitumor activity in the tumor microenvironments.Results We defined three different immunophenotypes and elucidated how immune cell interactions in immune subtypes vary with the background of the immune system. When the total number of mutations was standardized, no enrichment of new epitopes was detected in immunocompetent phenotypes. These observations suggest that mutations in Th-1 enriched IS3 tumors are essentially no more immunogenic than those in IS2 cancers. We also found that the expression patterns of key IFN mediators STAT1 and / or STAT3 were increased in tumors with DDR mutations (19 of ATM, ERCC1, Rb1, BRCA2, pole and TP53), which is a reflex activation of IFN pathway.Conclusions Three defined immune subtypes show different characteristics of immune cell infiltration, revealing different manifestations in anti-cancer immune function. That is to say, clinical biological events of differential tumors are associated to immune-phenotypes. The invasive phenotype was driven by somatic mutations across immune subtypes, and DDR defect may also influence the response of tumor immune subtypes. Our results suggested that the occurrence of pancreatic cancer is related to genetic factors of immunophenotype, providing information for clinical prognosis and outcome of pancreatic cancer.

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