Diverse effects of combined radiotherapy and EGFR inhibition with antibodies or TK inhibitors on local tumour control and correlation with EGFR gene expression

Gurtner, Kristin; Deuse, Yvonne; Bütof, Rebecca; Schaal, Katja; Eicheler, Wolfgang; Oertel, Reinhard; Grénman, Reidar; Thames, Howard D.; Yaromina, Ala; Baumann, Michaël; Krause, Mechthild

doi:10.1016/j.radonc.2011.05.035

Cited by 77 publications

(81 citation statements)

References 54 publications

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“…In a systematic comparison of different growth conditions, we show significant similarity of EGFR, ERK1/2, and Akt phosphorylation in SCC cells grown in 3D extracellular matrix (ECM) and as tumor xenografts in contrast to conventional monolayer cell cultures. In line with in vivo studies assessing cetuximab plus radiotherapy (7,9), cetuximab radiosensitized cells in a 3D, but not 2D, environment. Using phosphoproteome arrays, we observed strong induction of JNK2 phosphorylation potentially resulting from an interaction between cetuximab-inhibited EGFR and JNK-interacting protein-4 (JIP-4), which was identified in an immunoprecipitation-mass spectrometric approach.…”

Section: Introductionsupporting

confidence: 62%

“…Preclinical work showed the effectiveness of pharmacologic inhibitors and antibodies against EGFR in tumor cells from head and neck, lung, colon, and other cancers (3,(5)(6)(7)(8)(9)(10). Cetuximab, for example, is approved for use in combination with radiotherapy for treatment-na€ ve patients with locally advanced squamous cell carcinoma of the head and neck (HNSCC) and as monotherapy for recurrent or metastatic HNSCC (11,12).…”

Section: Introductionmentioning

confidence: 99%

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EGFR/JIP-4/JNK2 Signaling Attenuates Cetuximab-Mediated Radiosensitization of Squamous Cell Carcinoma Cells

et al. 2013

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EGF receptor (EGFR) promotes tumor growth as well as radio-and chemoresistance in various human malignancies including squamous cell carcinomas (SCC). In addition to deactivation of prosurvival signaling, cetuximab-mediated EGFR targeting might concomitantly induce self-attenuating signaling bypasses. Identification of such bypass mechanisms is key to improve the efficacy of targeted approaches. Here, we show great similarity of EGFR signaling and radiation survival in cetuximab-treated SCC cells grown in a more physiologic three-dimensional extracellular matrix and as tumor xenografts in contrast to conventional monolayer cell cultures. Using phosphoproteome arrays, we observed strong induction of JNK2 phosphorylation potentially resulting from cetuximab-inhibited EGFR through c-jun-NH 2 -kinase (JNK)-interacting protein-4 (JIP-4), which was identified using an immunoprecipitation-mass spectrometric approach. Inhibition of this signaling bypass by JIP-4 or JNK2 knockdown or pharmacologic JNK2 inhibition enhanced cetuximab efficacy and tumor cell radiosensitivity. Our findings add new facets to EGFR signaling and indicate signaling bypass possibilities of cancer cells to improve their survival on cetuximab treatment. By deactivation of cetuximab-self-attenuating JNK2-dependent signaling, the cytotoxicity, and radiosensitizing potential of cetuximab can be augmented.

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Section: Introductionsupporting

confidence: 62%

Section: Introductionmentioning

confidence: 99%

EGFR/JIP-4/JNK2 Signaling Attenuates Cetuximab-Mediated Radiosensitization of Squamous Cell Carcinoma Cells

et al. 2013

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“…65 Of note, tumours of this cell line were well perfused and showed the highest uptake of Cetuximab in the PET analysis. 65,68 However, they did not or only marginally responded to the combination of EBRT and cold Cetuximab, 65,67,69 which leads to the conclusion that the antibody functioned as a carrier of the radionuclide in the CIERT study but did not contribute by itself to the therapeutic effect. The result demonstrates the promising potential of CIERT if the radiolabelled agent accumulates in the target tumour and is well distributed.…”

Section: Pre-clinical Results: Promises and Challenges Of Combinationmentioning

confidence: 99%

“…However, the half-life is rather short. Furthermore, 67 Cu releases g-radiation directly following the b 2 -decay; thus, it can be used for SPECT, 51 but its production is difficult and expensive. 52 The positron emitters 86 Y and 124 I have been described controversially as PET nuclides since besides high b 1 -radiation energy they emit multiple highenergy g photons that cause so-called multiple coincidences disturbing PET imaging quality.…”

Section: Combination Of Internal and External Radiotherapymentioning

confidence: 99%

“…62,63,65 However, studying curative end points in preclinal trials is a pre-requisite for translation into clinical protocols with curative aim as promising results for tumour growth delay not always lead to enhanced control probability. 67,72 Additionally, the investigation of normal tissue toxicity should be performed in CIERT studies, as sparing of normal tissue dose is a major aspect of this treatment strategy. Again, only few studies paid attention to this complex issue, which may require the investigation of orthotopic tumour models.…”

Section: 65mentioning

confidence: 99%

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Improving external beam radiotherapy by combination with internal irradiation

Dietrich¹,

Koi²,

Zöphel³

et al. 2015

BJR

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The efficacy of external beam radiotherapy (EBRT) is dose dependent, but the dose that can be applied to solid tumour lesions is limited by the sensitivity of the surrounding tissue. The combination of EBRT with systemically applied radioimmunotherapy (RIT) is a promising approach to increase efficacy of radiotherapy. Toxicities of both treatment modalities of this combination of internal and external radiotherapy (CIERT) are not additive, as different organs at risk are in target. However, advantages of both single treatments are combined, for example, precise high dose delivery to the bulk tumour via standard EBRT, which can be increased by addition of RIT, and potential targeting of micrometastases by RIT. Eventually, theragnostic radionuclide pairs can be used to predict uptake of the radiotherapeutic drug prior to and during therapy and find individual patients who may benefit from this treatment. This review aims to highlight the outcome of pre-clinical studies on CIERT and resultant questions for translation into the clinic. Few clinical data are available until now and reasons as well as challenges for clinical implementation are discussed.

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Restoration of circPSMC3 sensitizes gefitinib‐resistant esophageal squamous cell carcinoma cells to gefitinib by regulating miR‐10a‐5p/PTEN axis

Zhu

Cao

2020

Cell Biology International

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Circular RNAs (circRNAs) has been shown to play an important role in the progression of various cancers. However, the function and underlying mechanisms of circRNAs affecting chemotherapy resistance in esophageal squamous cell carcinoma (ESCC) remain largely unknown. In this study, we used gefitinib‐resistant (GR) ESCC cells to investigate the function of circPSMC3 and clarify the underlying mechanism in chemotherapy resistance in ESCC. The results suggested that circPSMC3 expression was downregulated, but miR‐10a‐5p was upregulated in ESCC tissues and cells, as well as in GR ESCC cells. CircPSMC3 overexpression increased the sensitivity of ESCC cells to gefitinib, as indicated by reduced half maximal inhibitory concentration value, increased apoptosis rate and cleaved caspase‐3 protein expression. CircPSMC3 directly interacted with miR‐10a‐5p and inhibited the expression of miR‐10a‐5p. Phosphatase and tensin homolog (PTEN) was a direct target of miR‐10a‐5p and circPSMC3 promoted PTEN expression via decreasing miR‐10a‐5p level. Moreover, the effect of circPSMC3 on resistance of GR ESCC cells to gefitinib was remarkably reduced by restoration of miR‐10a‐5p and downregultion of PTEN. Taken together, these observations suggested that upregulation of circPSMC3 overcame resistance of GR ESCC cells to gefitinib by modulating the miR‐10a‐5p/PTEN axis, which provide a new therapeutic strategy for overcoming gefitinib resistance in ESCC.

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Diverse effects of combined radiotherapy and EGFR inhibition with antibodies or TK inhibitors on local tumour control and correlation with EGFR gene expression

Cited by 77 publications

References 54 publications

EGFR/JIP-4/JNK2 Signaling Attenuates Cetuximab-Mediated Radiosensitization of Squamous Cell Carcinoma Cells

EGFR/JIP-4/JNK2 Signaling Attenuates Cetuximab-Mediated Radiosensitization of Squamous Cell Carcinoma Cells

Improving external beam radiotherapy by combination with internal irradiation

Restoration of circPSMC3 sensitizes gefitinib‐resistant esophageal squamous cell carcinoma cells to gefitinib by regulating miR‐10a‐5p/PTEN axis

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