Targeting Notch to overcome radiation resistance

Yahyanejad, Sanaz; Theys, Jan; Vooijs, Marc

doi:10.18632/oncotarget.6714

Cited by 51 publications

(46 citation statements)

References 202 publications

(207 reference statements)

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“…In our study, PyClone analysis suggested that cells harboring NOTCH1 mutations were sensitive to radiation, whereas those harboring EGFR and MGA mutations were resistant to radiation. Recent studies suggest that activation of the NOTCH signaling pathway is related to radiation resistance in tumor cells (19)(20)(21). OncodriveROLE, a machine learning-based approach, indicated that the NOTCH1 p.Cys1374Tyr mutation, as detected in our study, is a "loss-of-function" mutation (22,23).…”

Section: Discussionsupporting

confidence: 63%

Elucidation of radiation-resistant clones by a serial study of intratumor heterogeneity before and after stereotactic radiotherapy in lung cancer

et al. 2017

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Stereotactic radiotherapy (SRT) for inoperable stage I non-small cell lung cancer has shown promising results and is now an alternative therapy for this disease. Several reports have detailed changes in mutation profiles after treatment with chemotherapy; however, such changes after SRT for lung cancer have not been reported. A patient who received SRT for lung cancer developed local recurrence 9 months after treatment and underwent surgery in our department. Using bronchoscopically biopsied and surgically resected specimens, we performed targeted sequencing of 53 lung cancer-related genes and compared the tumor mutation profiles before and after SRT. Identical mutations were detected from tumor specimens collected before and after SRT, and the specimens were confirmed to be clonal. However, the number of mutations decreased after SRT, suggesting that it induced mutation selection. Analyses of the statistical inference of clonal population structure showed that this evolving heterogeneous genomic landscape may be caused by heterogeneous responsiveness to SRT.

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Section: Discussionsupporting

confidence: 63%

Elucidation of radiation-resistant clones by a serial study of intratumor heterogeneity before and after stereotactic radiotherapy in lung cancer

et al. 2017

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“…γ-secretase inhibitors (GSI) effectively inhibit the NOTCH pathway in basic and pre-clinical research as well as clinical trials [13–14]. Inhibition of NOTCH signaling in glioma stem cells has been shown to impair the tumorigenic capacity of these cells and enhance their radiation and chemo-sensitivity [15–18]. Importantly, NOTCH inhibition has also been linked to TMZ-resistance through the EGF containing fibulin-like extracellular matrix protein 1 (EFEMP1) [19].…”

Section: Introductionmentioning

confidence: 99%

NOTCH blockade combined with radiation therapy and temozolomide prolongs survival of orthotopic glioblastoma

et al. 2016

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Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. The current standard of care includes surgery followed by radiotherapy (RT) and chemotherapy with temozolomide (TMZ). Treatment often fails due to the radiation resistance and intrinsic or acquired TMZ resistance of a small percentage of cells with stem cell-like behavior (CSC). The NOTCH signaling pathway is expressed and active in human glioblastoma and NOTCH inhibitors attenuate tumor growth in vivo in xenograft models. Here we show using an image guided micro-CT and precision radiotherapy platform that a combination of the clinically approved NOTCH/γ-secretase inhibitor (GSI) RO4929097 with standard of care (TMZ + RT) reduces tumor growth and prolongs survival compared to dual combinations. We show that GSI in combination with RT and TMZ attenuates proliferation, decreases 3D spheroid growth and results into a marked reduction in clonogenic survival in primary and established glioma cell lines. We found that the glioma stem cell marker CD133, SOX2 and Nestin were reduced following combination treatments and NOTCH inhibitors albeit in a different manner. These findings indicate that NOTCH inhibition combined with standard of care treatment has an anti-glioma stem cell effect which provides an improved survival benefit for GBM and encourages further translational and clinical studies.

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“…Notch signaling substantially impacts tumor initiation, progression, and treatment response, and combining Notch therapeutics with radiotherapy may result in synergistic improvements in various cancers, including cutaneous squamous cell carcinomas (SCCs) . Radio‐resistance is a great obstacle for NPC management .…”

Section: Discussionmentioning

confidence: 99%

“…The Notch signaling pathway is of significance in modulating cell fates, including cell proliferation and cell differentiation . New evidence indicated that the Notch signaling pathway plays an important role in mediating radiotherapy resistance of tumor cells, such as brain, lung and breast tumors . The Notch signaling pathway is also identified as a cancer therapeutic target in renal cell carcinoma, gastric cancer, and breast cancer given its self‐renewal and differentiation in tumor cells .…”

Section: Introductionmentioning

confidence: 99%

“…In addition, Numb is crucial to cell fate as a tumor suppressor during cancer progression, such as triple‐negative breast cancer . The Notch signaling pathway can regulate radiation resistance in radiotherapy, which is beneficial for numerous cancer patients, such as breast cancer and lung cancer patients . The Notch signaling pathway has the potential to affect chemotherapeutic agent resistance in gastric cancer as well as head and neck cancer .…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of the Numb/Notch signaling pathway increases radiation sensitivity in human nasopharyngeal carcinoma cells

Shen

Zeng

2019

The Kaohsiung J of Med Scie

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Radiation therapy is the primary treatment for primary nasopharyngeal carcinoma (NPC). The aim of this study is to identify the effect of the Numb/Notch signaling pathway on radiation sensitivity in human NPC cells. NPC tissues and normal nasopharyngeal tissues were collected. To evaluate the regulatory effects of the Numb/Notch signaling pathway, NPC cells were subjected to radiotherapy and various doses of the Numb/Notch signaling pathway inhibitor gamma secretase inhibitor (GSI). Next, the expression of Notch and Numb proteins was determined in NPC tissues and normal nasopharyngeal tissues, and the correlation of Notch and Numb protein expression with the clinicopathological features of NPC tissues was analyzed.Then, the effect of radiotherapy on NPC cell survival rate, survival fraction, apoptosis rate, proliferation, migration, and invasion as well as Numb/Notch signaling pathwayrelated molecules was detected. The results demonstrated that the Numb/Notch signaling pathway was activated in NPC tissues. Following treatment with radiotherapy and GSI, the Numb/Notch signaling pathway was inhibited. In addition, the NPC cell survival rate, survival fraction, cell proliferation, migration, and invasion were decreased, whereas the colony number and apoptosis rate were increased. Following radiotherapy and GSI treatment, Numb expression was increased, whereas Notch1, Hes1, Jagged1, and c-Myc expression was decreased. However, the greatest difference was noted upon treatment with radiotherapy +15 μM GSI. The results reported in this study suggest that a high dose of the inhibitor of the Numb/Notch signaling pathway GSI increased the radiation sensitivity in human NPC cells.

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Targeting Notch to overcome radiation resistance

Cited by 51 publications

References 202 publications

Elucidation of radiation-resistant clones by a serial study of intratumor heterogeneity before and after stereotactic radiotherapy in lung cancer

Elucidation of radiation-resistant clones by a serial study of intratumor heterogeneity before and after stereotactic radiotherapy in lung cancer

NOTCH blockade combined with radiation therapy and temozolomide prolongs survival of orthotopic glioblastoma

Inhibition of the Numb/Notch signaling pathway increases radiation sensitivity in human nasopharyngeal carcinoma cells

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