NF-κB signaling mediates acquired resistance after PARP inhibition

Nakagawa, Yuko; Sedukhina, Anna S.; Okamoto, Naoki; Nagasawa, Satoi; Suzuki, Nao; Ohta, Tomohiko; Hattori, Hiroyoshi; Roche-Molina, Marta; Narvaez, A.J.; Jeyasekharan, Anand D.; Bernal, Juan A.; Sato, Ko

doi:10.18632/oncotarget.2868

Cited by 38 publications

(47 citation statements)

References 30 publications

(47 reference statements)

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“…The affected cells then enter apoptosis. PARP inhibitor-resistant breast and ovarian cancer cell lines harboring BRCA1 mutation were used to study gene expression by RNA sequencing (249). Pathway analysis showed that ∼50% of the differentially expressed genes were NF-κBregulated genes and that TNFα was the upstream regulator of several of them.…”

Section: Poly-adenosine Diphosphate (Adp) Ribose Polymerase (Parp) Inmentioning

confidence: 99%

“…It was also demonstrated that treatment of PARP inhibitor-resistant cells with bortezomib induced cell death to a greater extent than the parental cell line, confirming the involvement of the NF-κB pathway in the resistant phenotype. Bortezomib treatment increases PARP inhibitor sensitivity of the resistant cell lines, suggesting a possible therapeutic combination in the clinical setting (249).…”

Section: Poly-adenosine Diphosphate (Adp) Ribose Polymerase (Parp) Inmentioning

confidence: 99%

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Tumor Necrosis Factor α Blockade: An Opportunity to Tackle Breast Cancer

et al. 2020

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Breast cancer is the most frequently diagnosed cancer and the principal cause of mortality by malignancy in women and represents a main problem for public health worldwide. Tumor necrosis factor α (TNFα) is a pro-inflammatory cytokine whose expression is increased in a variety of cancers. In particular, in breast cancer it correlates with augmented tumor cell proliferation, higher malignancy grade, increased occurrence of metastasis and general poor prognosis for the patient. These characteristics highlight TNFα as an attractive therapeutic target, and consequently, the study of soluble and transmembrane TNFα effects and its receptors in breast cancer is an area of active research. In this review we summarize the recent findings on TNFα participation in luminal, HER2-positive and triple negative breast cancer progression and metastasis. Also, we describe TNFα role in immune response against tumors and in chemotherapy, hormone therapy, HER2-targeted therapy and anti-immune checkpoint therapy resistance in breast cancer. Furthermore, we discuss the use of TNFα blocking strategies as potential therapies and their clinical relevance for breast cancer. These TNFα blocking agents have long been used in the clinical setting to treat inflammatory and autoimmune diseases. TNFα blockade can be achieved by monoclonal antibodies (such as infliximab, adalimumab, etc.), fusion proteins (etanercept) and dominant negative proteins (INB03). Here we address the different effects of each compound and also analyze the use of potential biomarkers in the selection of patients who would benefit from a combination of TNFα blocking agents with HER2-targeted treatments to prevent or overcome therapy resistance in breast cancer.

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Section: Poly-adenosine Diphosphate (Adp) Ribose Polymerase (Parp) Inmentioning

confidence: 99%

Section: Poly-adenosine Diphosphate (Adp) Ribose Polymerase (Parp) Inmentioning

confidence: 99%

Tumor Necrosis Factor α Blockade: An Opportunity to Tackle Breast Cancer

et al. 2020

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“…They intend to exploit synergistic effects of the agents or to overcome cytostatic resistance of the cancer cells. In the latter respect, ataxia telangiectasia and Rad3-related protein, mTOR, and NFκB pathway inhibitors were found to be effective [119,139,140].…”

Section: Open Questions and Future Directionsmentioning

confidence: 99%

Role of Akt Activation in PARP Inhibitor Resistance in Cancer

Gallyas

Sümegi

Szabó

2020

Cancers

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Poly(ADP-ribose) polymerase (PARP) inhibitors have recently been introduced in the therapy of several types of cancers not responding to conventional treatments. However, de novo and acquired PARP inhibitor resistance is a significant limiting factor in the clinical therapy, and the underlying mechanisms are not fully understood. Activity of the cytoprotective phosphatidylinositol-3 kinase (PI3K)-Akt pathway is often increased in human cancer that could result from mutation, expressional change, or amplification of upstream growth-related factor signaling elements or elements of the Akt pathway itself. However, PARP-inhibitor-induced activation of the cytoprotective PI3K-Akt pathway is overlooked, although it likely contributes to the development of PARP inhibitor resistance. Here, we briefly summarize the biological role of the PI3K-Akt pathway. Next, we overview the significance of the PARP-Akt interplay in shock, inflammation, cardiac and cerebral reperfusion, and cancer. We also discuss a recently discovered molecular mechanism that explains how PARP inhibition induces Akt activation and may account for apoptosis resistance and mitochondrial protection in oxidative stress and in cancer.

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“…Upregulation of the NF‐κB signaling pathway upon PARPi treatment is seen in ovarian cancer cell lines. Although the mechanism for such upregulation is not exactly determined but cotreatment with the NF‐κB and PARPi reversed the acquired resistance . Another approach to overcome the resistance for PARPi proposed a combinatorial therapy using ABT‐888 and vorinostat (a histone deacetylase inhibitor).…”

Section: Resistance To Parp Inhibitors: An Emerging Problem In Its CLmentioning

confidence: 99%

“…Although the mechanism for such upregulation is not exactly determined but cotreatment with the NF-κB and PARPi reversed the acquired resistance. 128 Another approach to overcome the resistance for PARPi proposed a combinatorial therapy using ABT-888 and vorinostat (a histone deacetylase inhibitor). Vorinostat sensitizes PARPi resistance cell lines to 6-thioguanine and this effect was due to increase in the phosphorylation status of Eukaryotic Initiation Factor 2 (eIF2α).…”

Section: Resistance To Parp Inhibitors: An Emerging Problem In Its CLmentioning

confidence: 99%

Therapeutic Targeting of Poly(ADP‐Ribose) Polymerase‐1 (PARP1) in Cancer: Current Developments, Therapeutic Strategies, and Future Opportunities

Rajawat

Shukla

Mishra

2017

Medicinal Research Reviews

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Poly(ADP-ribose) polymerase-1 (PARP-1) plays a central role in numerous cellular processes including DNA repair, replication, and transcription. PARP interacts directly, indirectly or via PARylation with various oncogenic proteins and regulates several transcription factors thereby modulating carcinogenesis. Therapeutic inhibition of PARP is therefore perceived as a promising anticancer strategy and a number of PARP inhibitors (PARPi) are currently under development and clinical evaluation. PARPi inhibit the DNA repair pathway and thus form the concept of synthetic lethality in cancer therapeutics. Preclinical and clinical studies have shown the potential of PARPi as chemopotentiator, radiosensitizer, or as adjuvant therapeutic agents. Recent studies have shown that PARP-1 could be either oncogenic or tumor suppressive in different cancers. PARP inhibitor resistance is also a growing concern in the clinical setting. Recently, changes in the levels of PARP-1 activity or expression in cancer patients have provided the basis for consideration of PARP-1 regulatory proteins as potential biomarkers. This review focuses on the current developments related to the role of PARP in cancer progression, therapeutic strategies targeting PARP-associated oncogenic signaling, and future opportunities in use of PARPi in anticancer therapeutics.

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NF-κB signaling mediates acquired resistance after PARP inhibition

Cited by 38 publications

References 30 publications

Tumor Necrosis Factor α Blockade: An Opportunity to Tackle Breast Cancer

Tumor Necrosis Factor α Blockade: An Opportunity to Tackle Breast Cancer

Role of Akt Activation in PARP Inhibitor Resistance in Cancer

Therapeutic Targeting of Poly(ADP‐Ribose) Polymerase‐1 (PARP1) in Cancer: Current Developments, Therapeutic Strategies, and Future Opportunities

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