Targeting Epidermal Growth Factor Receptor–Associated Signaling Pathways in Non–Small Cell Lung Cancer Cells: Implication in Radiation Response

Choi, Eun Jung; Ryu, Yun Kyeong; Kim, So Yeon; Wu, Hong Gyun; Kim, Jae Sung; Kim, Il Han; Kim, In Ah

doi:10.1158/1541-7786.mcr-09-0507

Cited by 67 publications

(61 citation statements)

References 33 publications

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“…1). Our results and accumulated reports from other laboratories indicate that radiosensitization by targeting PI3K or Akt1 (2-5) is a consequence of impaired DNA double-strand break (DNA-DSB) repair and subsequent reproductive cell death (6).…”

Section: Introductionsupporting

confidence: 66%

Akt Promotes Post-Irradiation Survival of Human Tumor Cells through Initiation, Progression, and Termination of DNA-PKcs–Dependent DNA Double-Strand Break Repair

Toulany

Lee

Fattah

et al. 2012

Molecular Cancer Research

151

155

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Akt phosphorylation has previously been described to be involved in mediating DNA damage repair through the nonhomologous end-joining (NHEJ) repair pathway. Yet the mechanism how Akt stimulates DNA-protein kinase catalytic subunit (DNA-PKcs)-dependent DNA double-strand break (DNA-DSB) repair has not been described so far. In the present study, we investigated the mechanism by which Akt can interact with DNA-PKcs and promote its function during the NHEJ repair process. The results obtained indicate a prominent role of Akt, especially Akt1 in the regulation of NHEJ mechanism for DNA-DSB repair. As shown by pull-down assay of DNA-PKcs, Akt1 through its C-terminal domain interacts with DNA-PKcs. After exposure of cells to ionizing radiation (IR), Akt1 and DNA-PKcs form a functional complex in a first initiating step of DNA-DSB repair. Thereafter, Akt plays a pivotal role in the recruitment of AKT1/DNA-PKcs complex to DNA duplex ends marked by Ku dimers. Moreover, in the formed complex, Akt1 promotes DNA-PKcs kinase activity, which is the necessary step for progression of DNA-DSB repair. Akt1-dependent DNA-PKcs kinase activity stimulates autophosphorylation of DNA-PKcs at S2056 that is needed for efficient DNA-DSB repair and the release of DNA-PKcs from the damage site. Thus, targeting of Akt results in radiosensitization of DNA-PKcs and Ku80 expressing, but not of cells deficient for, either of these proteins. The data showed indicate for the first time that Akt through an immediate complex formation with DNA-PKcs can stimulate the accumulation of DNA-PKcs at DNA-DSBs and promote DNA-PKcs activity for efficient NHEJ DNA-DSB repair. Mol Cancer Res; 10(7); 945-57. Ó2012 AACR. IntroductionThe serine/threonine kinase Akt/PKB is expressed as 3 isoforms, Akt1/PKBa, Akt2/PKBb and Akt3/PKBg. Akt activation is efficiently induced by ionizing radiation (IR) or by growth factors, such as EGF receptor (EGFR) ligands, through the activation of phosphoinositide 3-kinase (PI3K; ref. 1). Our results and accumulated reports from other laboratories indicate that radiosensitization by targeting PI3K or Akt1 (2-5) is a consequence of impaired DNA

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Section: Introductionsupporting

confidence: 66%

Akt Promotes Post-Irradiation Survival of Human Tumor Cells through Initiation, Progression, and Termination of DNA-PKcs–Dependent DNA Double-Strand Break Repair

Toulany

Lee

Fattah

et al. 2012

Molecular Cancer Research

151

155

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“…Lack of responsiveness to EGFR inhibition might be linked to the Kras mutational status; however, the specific role of Kras in NSCLC for the sensitivity to EGFR inhibitors alone and in combination with radiotherapy is still controversial (46)(47)(48)(49). We used the EGFR phosphorylation status as surrogate marker to determine shedding of ADAM17-mediated EGFR ligands.…”

Section: Discussionmentioning

confidence: 99%

Secretome Signature Identifies ADAM17 as Novel Target for Radiosensitization of Non–Small Cell Lung Cancer

Sharma

Bender

Zimmermann

et al. 2016

Clinical Cancer Research

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Purpose: Ionizing radiation (IR) induces intracellular signaling processes as part of a treatment-induced stress response. Here we investigate IR-induced ADAM17 activation and the role of ADAM17-shed factors for radiation resistance in non-small cell lung cancer.Experimental Design: Large-scale secretome profiling was performed using antibody arrays. Secretion kinetics of ADAM17 substrates was determined using ELISA across multiple in vitro and in vivo models of non-small cell lung cancer. Clonogenic survival and tumor xenograft assays were performed to determine radiosensitization by ADAM17 inhibition.Results: On the basis of a large-scale secretome screening, we investigated secretion of auto-or paracrine factors in non-small cell lung cancer in response to irradiation and discovered the ADAM17 network as a crucial mediator of resistance to IR. Irradiation induced a dose-dependent increase of furin-mediated cleavage of the ADAM17 proform to active ADAM17, which resulted in enhanced ADAM17 activity in vitro and in vivo. Genetic or pharmacologic targeting of ADAM17 suppressed IR-induced shedding of secreted factors, downregulated ErbB signaling in otherwise cetuximab-resistant target cells, and enhanced IRinduced cytotoxicity. The combined treatment modality of IR with the ADAM17 inhibitor TMI-005 resulted in a supra-additive antitumor response in vivo demonstrating the potential of ADAM17 targeting in combination with radiotherapy.Conclusions: Radiotherapy activates ADAM17 in non-small cell lung cancer, which results in shedding of multiple survival factors, growth factor pathway activation, and IR-induced treatment resistance. We provide a sound rationale for repositioning ADAM17 inhibitors as short-term adjuvants to improve the radiotherapy outcome of non-small cell lung cancer. Clin Cancer Res; 22(17); 4428-39. Ó2016 AACR.

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“…Nevertheless, radiation remains an effective modality for the treatment of many tumor types, thus emphasizing a potentially valuable role for nonapoptotic responses to treatment. In keeping with this, emerging evidence indicates that apoptosis is not the sole or even predominant mechanism through which some DNA-damaging agents and PI3K/mTOR pathway inhibitors increase radiosensitivity (20)(21)(22)(23). Thus, nonapoptotic mechanisms may be a significant factor in radiosensitization of epithelial cancer cells by BEZ235.…”

Section: Introductionmentioning

confidence: 93%

Inhibition of DNA-Dependent Protein Kinase Induces Accelerated Senescence in Irradiated Human Cancer Cells

Azad

Jackson

Cullinane

et al. 2011

Molecular Cancer Research

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DNA-dependent protein kinase (DNA-PK) plays a pivotal role in the repair of DNA double-strand breaks (DSB) and is centrally involved in regulating cellular radiosensitivity. Here, we identify DNA-PK as a key therapeutic target for augmenting accelerated senescence in irradiated human cancer cells. We find that BEZ235, a novel inhibitor of DNA-PK and phosphoinositide 3-kinase (PI3K)/mTOR, abrogates radiation-induced DSB repair resulting in cellular radiosensitization and growth delay of irradiated tumor xenografts. Importantly, radiation enhancement by BEZ235 coincides with a prominent p53-dependent accelerated senescence phenotype characterized by positive b-galactosidase staining, G 2 -M cell-cycle arrest, enlarged and flattened cellular morphology, and increased p21 expression and senescence-associated cytokine secretion. Because this senescence response to BEZ235 is accompanied by unrepaired DNA DSBs, we examined whether selective targeting of DNA-PK also induces accelerated senescence in irradiated cells. Significantly, we show that specific pharmacologic inhibition of DNA-PK, but not PI3K or mTORC1, delays DSB repair leading to accelerated senescence after radiation. We additionally show that PRKDC knockdown using siRNA promotes a striking accelerated senescence phenotype in irradiated cells comparable with that of BEZ235. Thus, in the context of radiation treatment, our data indicate that inhibition of DNA-PK is sufficient for the induction of accelerated senescence. These results validate DNA-PK as an important therapeutic target in irradiated cancer cells and establish accelerated senescence as a novel mechanism of radiosensitization induced by DNA-PK blockade. Mol Cancer Res; 9(12); 1696-707. Ó2011 AACR.

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Targeting Epidermal Growth Factor Receptor–Associated Signaling Pathways in Non–Small Cell Lung Cancer Cells: Implication in Radiation Response

Cited by 67 publications

References 33 publications

Akt Promotes Post-Irradiation Survival of Human Tumor Cells through Initiation, Progression, and Termination of DNA-PKcs–Dependent DNA Double-Strand Break Repair

Akt Promotes Post-Irradiation Survival of Human Tumor Cells through Initiation, Progression, and Termination of DNA-PKcs–Dependent DNA Double-Strand Break Repair

Secretome Signature Identifies ADAM17 as Novel Target for Radiosensitization of Non–Small Cell Lung Cancer

Inhibition of DNA-Dependent Protein Kinase Induces Accelerated Senescence in Irradiated Human Cancer Cells

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