The response of head and neck squamous cell carcinoma to cetuximab treatment depends on Aurora kinase A polymorphism

Pickhard, Anja; Siegl, Michael; Baumann, Alexander; Huhn, Maximilian; Wirth, Markus; Reiter, Rudolf; Rudelius, Martina; Piontek, Guido; Brockhoff, Gero

doi:10.18632/oncotarget.2117

Cited by 19 publications

(27 citation statements)

References 41 publications

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“…Various strategies have been developed to disrupt EGFR function and to interfere with downstream signaling ( 11 , 12 ). Anti-EGFR mAbs and EGFR inhibitors have been investigated the most extensively ( 3 , 5 , 13 ).…”

Section: Introductionmentioning

confidence: 99%

Synergistic inhibitory effects of cetuximab and curcumin on human cisplatin‑resistant oral cancer CAR cells through intrinsic apoptotic process

Chen

Chiang³

et al. 2018

Oncol Lett

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Cetuximab, an epidermal growth factor receptor (EGFR)-targeting monoclonal antibody (mAb), is a novel targeted therapy for the treatment of patients with oral cancer. Cetuximab can be used in combination with chemotherapeutic agents to prolong the overall survival rates of patients with oral cancer. Curcumin is a traditional Chinese medicine, and it has been demonstrated to have growth-inhibiting effects on oral cancer cells. However, information regarding the combination of cetuximab and curcumin in drug-resistant oral cancer cells is lacking, and its underlying mechanism remains unclear. The purpose of the present study was to explore the oral anticancer effects of cetuximab combined with curcumin on cisplatin-resistant oral cancer CAR cell apoptosis in vitro. The results demonstrated that combination treatment synergistically potentiated the effect of cetuximab and curcumin on the suppression of cell viability and induction of apoptosis in CAR cells. Cetuximab and curcumin combination induced apoptosis and dramatically increased caspase-3 and caspase-9 activities compared with singular treatment. Combination treatment also markedly suppressed the protein expression levels of EGFR and mitogen-activated protein kinases (MAPKs) signaling (phosphorylation of ERK, JNK and p38). The results demonstrated that co-treatment with cetuximab and curcumin exerts synergistic oral anticancer effects on CAR cells through the suppression of the EGFR signaling by regulation of the MAPK pathway.

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Section: Introductionmentioning

confidence: 99%

Synergistic inhibitory effects of cetuximab and curcumin on human cisplatin‑resistant oral cancer CAR cells through intrinsic apoptotic process

Chen

Chiang³

et al. 2018

Oncol Lett

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“…The Aurora-Kinase C is mainly expressed in the testicles and supports the Aurora-Kinase B function [ 3 ]. Elevated Aurora-Kinase expression has been found in a number of malignancies [ 4 ], amongst them HNSCC [ 5 , 6 ]. Moreover, it has been shown that the AurkA Phe 31 -Ile polymorphism enhances esophageal cancer progression [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

The Aurora-Kinase A Phe31-Ile polymorphism as possible predictor of response to treatment in head and neck squamous cell carcinoma

et al. 2018

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Recently the Aurora-Kinases (Aurk) moved into the focus as novel disease related biomarkers and therapeutic targets. Elevated Aurora-Kinase expression has been found in a number of malignancies, amongst them HNSCC. For esophageal cancer, the AurkA Phe31-Ile polymorphism has previously been associated with tumor progression. Here we evaluated the treatment efficiency of HNSCC cell radiation as a function of Aurora-Kinases in HNSCC cell lines. Moreover, we investigated a potential sensitization to radiation by a cell treatment with the inhibitors Alisertib, Barasertib, Docetaxel and VX-680.In parallel the radiation dependent expression and regulation of AurkA/B, p-Akt Ser 473 and Survivin and the AurkA polymorphism were investigated in primary tumor samples. We identified a high-risk collective with elevated AurkA and Survivin or AurkA and p-Akt Ser 473 expression.High AurkA, AurkB, and p-Akt Ser 473 expression was exclusively found in the heterozygous cell line. We found a polymorphism dependent sensitivity to treatments with different Aurk inhibitors: The homozygous cell line UD-SCC-5 could be sensitized to radiation with Docetaxel in combination with any of the Aurora-Kinase inhibitors. In contrast, treatment with Docetaxel or radiation did not enhance the inhibitory effect of Barasertib or VX-680 in the heterozygous SAS cell line.These findings indicate that the Aurora-Kinase A Phe31-Ile-polymorphism is a possibly predictive factor for response to radiation in combination with Docetaxel and Aurora-Kinase inhibitor treatments.

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“…Thus, the receptor should be internalized and down-regulated, leading to the inhibition of downstream signaling cascade [21]. This paradoxical phosphorylation of EGFR by Cetuximab treatment has been described in the literature [22, 23]. …”

Section: Discussionmentioning

confidence: 99%

Epidermal growth factor receptor variant III in head and neck squamous cell carcinoma is not relevant for targeted therapy and irradiation

et al. 2017

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BackgroundThe epidermal growth factor receptor (EGFR) is an important regulator of cell growth and survival, and is highly variable in tumor cells. The most prevalent variation of the EGFR extracellular domain is the EGFR variant III (EGFRvIII). Some studies imply that EGFRvIII may be responsible for the poor response to the monoclonal EGFR-antibody Cetuximab, used therapeutically in head and neck squamous cell carcinoma (HNSCC). Due to inconsistent data in the literature regarding EGFRvIII prevalence and clinical relevance in HNSCC, especially its predictive value, we examined EGFRvIII-transfected cell lines and patient tissue samples.ResultsIn contrast to other recent publications, we were able to demonstrate EGFRvIII expression in HNSCC. However, we noted that the different detection methods yielded inconsistent results. Furthermore, our EGFRvIII transfected and EGFR wild type cell lines exhibited similar characteristics and response rates in the performed in vitro experiments.Materials and MethodsWe conducted various inhibition and combined irradiation experiments using three EGFRvIII-transfected cell lines. Moreover, a patient cohort of 149 cases consisting of formalin fixed and paraffin embedded (FFPE) and fresh-frozen specimens was assayed via reverse transcriptase PCR (rtPCR) with gel electrophoresis and sequencing for EGFRvIII prevalence. In the rtPCR assays, we used five previously published EGFRvIII primers and EGFRvIII-positive glioblastoma tissue as a positive control. In addition, immunohistochemical staining was conducted.ConclusionsEGFRvIII can be detected in HNSCC patient samples. Nevertheless, the low prevalence and similar response rates to targeted drugs and irradiation in vitro cast doubt regarding the clinical relevance of EGFRvIII in HNSCC.

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The response of head and neck squamous cell carcinoma to cetuximab treatment depends on Aurora kinase A polymorphism

Cited by 19 publications

References 41 publications

Synergistic inhibitory effects of cetuximab and curcumin on human cisplatin‑resistant oral cancer CAR cells through intrinsic apoptotic process

Synergistic inhibitory effects of cetuximab and curcumin on human cisplatin‑resistant oral cancer CAR cells through intrinsic apoptotic process

The Aurora-Kinase A Phe31-Ile polymorphism as possible predictor of response to treatment in head and neck squamous cell carcinoma

Epidermal growth factor receptor variant III in head and neck squamous cell carcinoma is not relevant for targeted therapy and irradiation

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