Interaction of Discoidin Domain Receptor 1 with a 14-3-3-Beclin-1-Akt1 Complex Modulates Glioblastoma Therapy Sensitivity

Vehlow, Anne; Klapproth, Erik; Jin, Sha; Hannen, Ricarda; Hauswald, Maria; Bartsch, Jörg W.; Nimsky, Christopher; Temme, Achim; Leitinger, Birgit; Cordes, Nils

doi:10.1016/j.celrep.2019.02.096

Cited by 54 publications

(49 citation statements)

References 57 publications

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“…Recently, DDR1 inhibition in a mouse model of pancreatic ductal adenocarcinoma increased tumor response to standard-of-care chemotherapy regimens (45). Similarly, DDR1 inhibition sensitized glioblastoma cells to radio-and chemotherapy resulting in prolonged patient survival (46). Therefore, in addition to LUAD, DDR1-associated chemoresistance has been observed in other tumors.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of DDR1 enhances in vivo chemosensitivity in KRAS-mutant lung adenocarcinoma

Nokin¹,

Darbo²,

Travert³

et al. 2020

JCI Insight

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Section: Discussionmentioning

confidence: 99%

Inhibition of DDR1 enhances in vivo chemosensitivity in KRAS-mutant lung adenocarcinoma

Nokin¹,

Darbo²,

Travert³

et al. 2020

JCI Insight

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“…Irradiation was performed at room temperature using single doses of 200 kV X-rays (Yxlon Y.TU 320; Yxlon, Hamburg, Germany; dose rate~1.3 Gy/min at 20 mA), filtered with 0.5 mm Cu, as described previously [47]. Dosimetry for quality assurance was performed using a Duplex dosimeter (PTW Freiburg; Freiburg, Germany) prior to irradiation.…”

Section: X-ray Irradiationmentioning

confidence: 99%

“…The mutated sites were confirmed by sequencing. Stable transfection of the synemin constructs was performed as published in [47] using lipofectamine2000 (Invitrogen) and G418 (#A1720, Sigma-Aldrich, Taufkirchen, Germany) for the selection of cells.…”

Section: Synenim Constructs and Stable Transfectionmentioning

confidence: 99%

The Intermediate Filament Synemin Regulates Non-Homologous End Joining in an ATM-Dependent Manner

Deville

Vehlow

Förster

et al. 2020

Cancers

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The treatment resistance of cancer cells is a multifaceted process in which DNA repair emerged as a potential therapeutic target. DNA repair is predominantly conducted by nuclear events; yet, how extra-nuclear cues impact the DNA damage response is largely unknown. Here, using a high-throughput RNAi-based screen in three-dimensionally-grown cell cultures of head and neck squamous cell carcinoma (HNSCC), we identified novel focal adhesion proteins controlling DNA repair, including the intermediate filament protein, synemin. We demonstrate that synemin critically regulates the DNA damage response by non-homologous end joining repair. Mechanistically, synemin forms a protein complex with DNA-PKcs through its C-terminal tail domain for determining DNA repair processes upstream of this enzyme in an ATM-dependent manner. Our study discovers a critical function of the intermediate filament protein, synemin in the DNA damage response, fundamentally supporting the concept of cytoarchitectural elements as co-regulators of nuclear events.

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“…The promitotic and adhesion-mediating discoidin domain receptor tyrosine kinase 1 (DDR1) plays a critical role in the modulation of GB therapy resistance. Inhibition of DDR1 combined with radiotherapy and TMZ treatment enhances the sensitivity of the GB treatment and prolongs survival, through a mechanism in which the 14-3-3–BECN1–AKT1 protein complex assembled with DDR1 promotes AKT/mTOR signaling pathways and is crucial for the regulation of autophagy-mediated therapy sensitivity ( 78 ).…”

Section: The Role Of Autophagy In Glioblastoma Therapy With the Phospmentioning

confidence: 99%

Therapeutic Potential of Autophagy in Glioblastoma Treatment With Phosphoinositide 3-Kinase/Protein Kinase B/Mammalian Target of Rapamycin Signaling Pathway Inhibitors

Qin

Zhang

et al. 2020

Front. Oncol.

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Glioblastoma (GB) is the most malignant and aggressive form of brain tumor, characterized by frequent hyperactivation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway. PI3K/AKT/mTOR inhibitors have a promising clinical efficacy theoretically. However, strong drug resistance is developed in GB against the PI3K/AKT/mTOR inhibitors due to the cytoprotective effect and the adaptive response of autophagy during the treatment of GB. Activation of autophagy by the PI3K/AKT/mTOR inhibitors not only enhances treatment sensitivity but also leads to cell survival when drug resistance develops in cancer cells. In this review, we analyze how to increase the antitumor effect of the PI3K/AKT/mTOR inhibitors in GB treatment, which is achieved by various mechanisms, among which targeting autophagy is an important mechanism. We review the dual role of autophagy in both GB therapy and resistance against inhibitors of the PI3K/AKT/mTOR signaling pathway, and further discuss the possibility of using combinations of autophagy and PI3K/AKT/mTOR inhibitors to improve the treatment efficacy for GB. Finally, we provide new perspectives for targeting autophagy in GB therapy.

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Interaction of Discoidin Domain Receptor 1 with a 14-3-3-Beclin-1-Akt1 Complex Modulates Glioblastoma Therapy Sensitivity

Abstract: Highlights d DDR1 and stem cell marker co-expression in GBM correlates with patient outcome d A DDR1-associated 14-3-3-Beclin-1-Akt1 complex induces prosurvival signaling d DDR1 targeting elicits autophagy-associated therapy sensitization

Cited by 54 publications

References 57 publications

Inhibition of DDR1 enhances in vivo chemosensitivity in KRAS-mutant lung adenocarcinoma

Inhibition of DDR1 enhances in vivo chemosensitivity in KRAS-mutant lung adenocarcinoma

The Intermediate Filament Synemin Regulates Non-Homologous End Joining in an ATM-Dependent Manner

Therapeutic Potential of Autophagy in Glioblastoma Treatment With Phosphoinositide 3-Kinase/Protein Kinase B/Mammalian Target of Rapamycin Signaling Pathway Inhibitors

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