Inhibition of ataxia telangiectasia related-3 (ATR) improves therapeutic index in preclinical models of non-small cell lung cancer (NSCLC) radiotherapy

Dunne, Victoria; Ghita, Mihaela; Small, D.; Coffey, Caroline B M; Weldon, Sinéad; Taggart, Clifford C.; Osman, Sarah; McGarry, Conor K.; Prise, Kevin M.; Hanna, G.G.; Butterworth, Karl T.

doi:10.1016/j.radonc.2017.06.025

Cited by 31 publications

(29 citation statements)

References 31 publications

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“…CONCORDE is the first platform trial of novel systemic treatment and RT in lung cancer patients [27]. As repair of radiation-induced DNA damage is thought to enable tumour cells to survive therapeutic radiation doses, there is a sound scientific rationale for the combination with DDRi, with supportive preclinical data [15][16][17][18]. Related translational research will exploit the rich, prospective datasets generated, spanning tissue-and plasma-based genomics, immunobiology, biochemical pathology and radiomics.…”

Section: Discussionmentioning

confidence: 99%

“…While the biology underpinning the intrinsic radioresistance of NSCLC remains incompletely defined, repair of radiation-induced DNA damage is considered a fundamental component [14] . These pathways are actionable [15] , [16] , [17] , [18] : potent novel agents targeting DNA damage response pathways are becoming clinically available [19] and strategies for synergistic combination of systemic agents with RT are being realised across tumours [20] , [21] , [22] , [23] , [24] . Careful, efficient and multidisciplinary clinical trial design is essential for accurate assessment of the toxicities associated with these new and challenging treatment paradigms, and to ensure that the maximum impact on therapeutic index is achieved [25] , [26] .…”

Section: Introductionmentioning

confidence: 99%

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CONCORDE: A phase I platform study of novel agents in combination with conventional radiotherapy in non-small-cell lung cancer

Walls

Oughton

Chalmers

et al. 2020

Clinical and Translational Radiation Oncology

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Lung cancer is the leading cause of cancer mortality worldwide and most patients are unsuitable for 'gold standard' treatment, which is concurrent chemoradiotherapy. CONCORDE is a platform study seeking to establish the toxicity profiles of multiple novel radiosensitisers targeting DNA repair proteins in patients treated with sequential chemoradiotherapy. Time-to-event continual reassessment will facilitate efficient dose-finding.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CONCORDE: A phase I platform study of novel agents in combination with conventional radiotherapy in non-small-cell lung cancer

Walls

Oughton

Chalmers

et al. 2020

Clinical and Translational Radiation Oncology

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“…While these are typically prescribed based on their activity as single agents, there is growing interest in specifically seeking to develop radiation sensitizing agents [23]. In this approach, agents are usually identified which seek to target specific parts of the radiation response pathway, such as genes involved in DNA repair [163,164,165]. While this approach has identified some radiation sensitizers, translation has been limited.…”

Section: Potential Impacts Of Modelling Advancesmentioning

confidence: 99%

Mechanistic Modelling of Radiation Responses

McMahon

Prise

2019

Cancers

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Radiobiological modelling has been a key part of radiation biology and therapy for many decades, and many aspects of clinical practice are guided by tools such as the linear-quadratic model. However, most of the models in regular clinical use are abstract and empirical, and do not provide significant scope for mechanistic interpretation or making predictions in novel cell lines or therapies. In this review, we will discuss the key areas of ongoing mechanistic research in radiation biology, including physical, chemical, and biological steps, and review a range of mechanistic modelling approaches which are being applied in each area, highlighting the possible opportunities and challenges presented by these techniques.

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“…One reason for the low survival rate of this malignancy is the uncontrolled proliferation and metastatic potential of NSCLC cells [5,6]. Radiotherapy (RT) is a powerful modality that is widely used in the clinical management of NSCLC [7,8]. However, NSCLC cells exhibit intrinsic or acquired resistance to RT, which leads to treatment failure and induces local recurrence of NSCLC [9,10].…”

Section: Introductionmentioning

confidence: 99%

CLPTM1L induces estrogen receptor β signaling-mediated radioresistance in non-small cell lung cancer cells

Chen

Jiang

et al. 2020

Cell Commun Signal

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Introduction Radioresistance is a major challenge in lung cancer radiotherapy, and new radiosensitizers are urgently needed. Estrogen receptor β (ERβ) is involved in the progression of non-small cell lung cancer (NSCLC), however, the role of ERβ in the response to radiotherapy in lung cancer remains elusive. In the present study, we investigated the mechanism underlying ERβ-mediated transcriptional activation and radioresistance of NSCLC cells. Methods Quantitative real-time PCR, western blot and immunohistochemistry were used to detect the expression of CLPTM1L, ERβ and other target genes. The mechanism of CLPTM1L in modulation of radiosensitivity was investigated by chromatin immunoprecipitation assay, luciferase reporter gene assay, immunofluorescence staining, confocal microscopy, coimmunoprecipitation and GST pull-down assays. The functional role of CLPTM1L was detected by function assays in vitro and in vivo. Results CLPTM1L expression was negatively correlated with the radiosensitivity of NSCLC cell lines, and irradiation upregulated CLPTM1L in radioresistant (A549) but not in radiosensitive (H460) NSCLC cells. Meanwhile, IR induced the translocation of CLPTM1L from the cytoplasm into the nucleus in NSCLC cells. Moreover, CLPTM1L induced radioresistance in NSCLC cells. iTRAQ-based analysis and cDNA microarray identified irradiation-related genes commonly targeted by CLPTM1L and ERβ, and CLPTM1L upregulated ERβ-induced genes CDC25A, c-Jun, and BCL2. Mechanistically, CLPTM1L coactivated ERβ by directly interacting with ERβ through the LXXLL NR (nuclear receptor)-binding motif. Functionally, ERβ silencing was sufficient to block CLPTM1L-enhanced radioresistance of NSCLC cells in vitro. CLPTM1L shRNA treatment in combination with irradiation significantly inhibited cancer cell growth in NSCLC xenograft tumors in vivo. Conclusions The present results indicate that CLPTM1L acts as a critical coactivator of ERβ to promote the transcription of its target genes and induce radioresistance of NSCLC cells, suggesting a new target for radiosensitization in NSCLC therapy.

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Inhibition of ataxia telangiectasia related-3 (ATR) improves therapeutic index in preclinical models of non-small cell lung cancer (NSCLC) radiotherapy

Abstract: Inhibition of ATR with AZD6738 in combination with radiotherapy increases tumour growth delay without observable augmentation of late radiation induced toxicity further underpinning translation towards clinical evaluation in NSCLC.

Cited by 31 publications

References 31 publications

CONCORDE: A phase I platform study of novel agents in combination with conventional radiotherapy in non-small-cell lung cancer

CONCORDE: A phase I platform study of novel agents in combination with conventional radiotherapy in non-small-cell lung cancer

Mechanistic Modelling of Radiation Responses

CLPTM1L induces estrogen receptor β signaling-mediated radioresistance in non-small cell lung cancer cells

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