Cetuximab sensitivity of head and neck squamous cell carcinoma xenografts is associated with treatment‐induced reduction in <scp>EGFR</scp>, p<scp>EGFR</scp>, and pSrc

Jedliński, Adam; Garvin, Stina; Johansson, Ann-Charlotte; Edqvist, Per‐Henrik; Pontén, Fredrik; Roberg, Karin

doi:10.1111/jop.12545

Cited by 6 publications

(8 citation statements)

References 21 publications

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“…Additionally, we have shown in our previous study that high sensitivity to cetuximab in UT-SCC-14 cell lines was associated with cetuximab-mediated reduction in pEGFR both in vivo and in vitro [39]. Nevertheless, neither inhibition of EGFR with cetuximab or HIF-1α knockdown could overcome the hypoxia-mediated decreased sensitivity to cetuximab in the UT-SCC-14 cell line compared to the LK0412 cell line.…”

Section: Discussionmentioning

confidence: 96%

Hypoxia Mediates Differential Response to Anti-EGFR Therapy in HNSCC Cells

Wiecheć

Hansson²,

Alexandersson³

et al. 2017

IJMS

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Despite advances in the head and neck squamous cell carcinoma (HNSCC) treatment modalities, drug resistance and cancer recurrence are often reported. Hypoxia signaling through hypoxia-inducible factor 1 (HIF-1) promotes angiogenesis and metastasis by inducing epithelial-mesenchymal-transition (EMT). The aim of this study was to evaluate the impact of hypoxia on response to therapy as well as EMT and expression of stem cell markers in HNSCC cells. Five HNSCC cell lines (UT-SCC-2, UT-SCC-14, LK0412, LK0827, and LK0923) were selected for this study. The treatment sensitivity for radiation, cisplatin, cetuximab, and dasatinib was assessed by crystal violet assay. Gene expression of EMT and cancer stem cell (CSC) markers as well as protein level of EGFR signaling molecules were analyzed by qPCR and western blotting, respectively. Unlike UT-SCC-14 and LK0827, the LK0412 cell line became significantly more sensitive to cetuximab in hypoxic conditions. This cetuximab sensitivity was efficiently reversed after suppression of HIF-1α with siRNA. Additionally, hypoxia-induced EMT and expression of stem cell markers in HNSCC cells was partially revoked by treatment with cetuximab or knockdown of HIF-1α. In summary, our study shows that hypoxia might have a positive influence on the anti-EGFR therapy effectiveness in HNSCC. However, due to heterogeneity of HNSCC lesions, targeting HIF-1α may not be sufficient to mediate such a response. Further studies identifying a trait of hypoxia-specific response to cetuximab in HNSCC are advisable.

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Section: Discussionmentioning

confidence: 96%

Hypoxia Mediates Differential Response to Anti-EGFR Therapy in HNSCC Cells

Wiecheć

Hansson²,

Alexandersson³

et al. 2017

IJMS

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“…In one of our earlier studies, sensitivity to cetuximab-treatment in UT-SCC-14 cells was associated with cetuximab-mediated reduction of pEGFR in vivo and in vitro (128). In the current study, pEGFR expression was similar in both normoxic and hypoxic conditions in this cell line.…”

Section: The Impact Of Hypoxia On Hnscc Cell Linessupporting

confidence: 57%

The impact of Survivin, WRAP53β, and Hypoxia on treatment response in Head and Neck Cancer

Tiefenböck-Hansson¹

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v ABSTRACTSquamous cell carcinoma (SCC) is the most common histological type of cancer in the head and neck region and arises in the epithelial mucosa of the upper aerodigestive tract.Approximately one and a half million people are living with the diagnosis. Despite efforts in prevention and advances in treatment, the 5-year survival rate still lies around 60%, and recurrences and second primary tumors remain a problem. Moreover, treatment responses vary from patient to patient, highlighting the need for individually tailored treatments. To make this possible, biomarkers predicting treatment outcome are needed to better guide treatment decisions.The aim of this thesis was to evaluate the expression of certain proteins and the frequency of certain SNPs (Single nucleotide polymorphisms) in tumor biopsies and cell cultures of head and neck squamous cell carcinomas (HNSCC), and to explore their potential as biomarkers for treatment outcome. Furthermore, we aimed to study the impact of hypoxia on treatment response, epithelial-to-mesenchymal transition (EMT), and induction of cancer stem cells (CSC).In papers I and II, we investigated two proteins, survivin and WRAP53β, using immunohistochemistry (IHC) in tumor biopsies from 40 patients categorized as Nonresponders or Responders to radiotherapy. High expression of survivin and nuclear expression of WRAP53β were significantly more prevalent in the Responder group. The combination of these two factors correlated strongest to overall survival, but not to a significantly higher extent compared to survivin alone. Moreover, when examined separately, a high percentage of p53-stained cells and the presence of the SNP FGFR4 Gln388Arg correlated to improved overall survival, whereas the SNP XPD Lys751Gln was associated with worse overall survival. The latter three showed no significant correlations to radiotherapy response. In paper III, the two ABSTRACT vi most promising proteins identified in papers I and II were analyzed in a study cohort of 149 tumor biopsies of glottic laryngeal SCC, categorized as T2N0-T3N0. In this patient group, no significant associations between survivin expression and survival could be found. However, expression of cytoplasmic WRAP53β was significantly linked to worse disease-free-survival (DSF) compared to nuclear WRAP53β or negative staining for WRAP53β. Positive expression of p16INK4a was found in 7% of the tumors. The prevalence of p16 INK4a was higher in younger patients (<60) and associated with absence of recurrence and longer DSF.In paper IV, five HNSCC cell lines were cultured in normoxic (20% O 2 ) and hypoxic (1% O 2 )conditions and changes in treatment response, EMT profile, and expression of CSC markers were examined. As expected, hypoxia induced EMT and to a certain extent expression of CSC markers. Silencing of the hypoxia-inducible-factor-1α (HIF-1α) only partly reversed these effects, suggesting that other mechanisms are involved. Whereas most cell lines became more resistant to treatment in hypoxia, one cell line (LK0412) ...

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“…The mice were treated intraperitoneally (i.p.) with VPA (200 mg/kg melted in water and diluted in a physiological solution, five times a week for two weeks), and/or CDDP (1 mg/kg melted in PBS 1X and diluted in a physiologic solution) based on previous reports ( Terranova-Barberio et al, 2016 ; Piro et al, 2019 ) and CX (1 mg/kg diluted in a physiologic solution) based on a pilot study (data not shown) and previous reports ( Jedlinski et al, 2017 ). The mice in the control group were treated with drugs vehicles.…”

Section: Methodsmentioning

confidence: 99%

Valproic Acid Synergizes With Cisplatin and Cetuximab in vitro and in vivo in Head and Neck Cancer by Targeting the Mechanisms of Resistance

Iannelli

Zotti

Roca

et al. 2020

Front. Cell Dev. Biol.

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Recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) is a devastating malignancy with a poor prognosis. The combination of cisplatin (CDDP) plus cetuximab (CX) is one of the standard first-line treatments in this disease. However, this therapeutic regimen is often associated with high toxicity and resistance, suggesting that new combinatorial strategies are needed to improve its therapeutic index. In our study, we evaluated the antitumor effects of valproic acid (VPA), a well-known antiepileptic agent with histone deacetylase inhibitory activity, in combination with CDDP/CX doublet in head and neck squamous cell carcinoma (HNSCC) models. We demonstrated, in HNSCC cell lines, but not in normal human fibroblasts, that simultaneous exposure to equitoxic doses of VPA plus CDDP/CX resulted in a clear synergistic antiproliferative and pro-apoptotic effects. The synergistic antitumor effect was confirmed in four different 3D-self-assembled spheroid models, suggesting the ability of the combined approach to affect also the cancer stem cells compartment. Mechanistically, VPA enhanced DNA damage in combination treatment by reducing the mRNA expression of ERCC Excision Repair 1, a critical player in DNA repair, and by increasing CDDP intracellular concentration via upregulation at transcriptional level of CDDP influx channel copper transporter 1 and downregulation of the ATPAse ATP7B involved in CDDP-export. Valproic acid also induced a dose-dependent downregulation of epidermal growth factor receptor (EGFR) expression and of MAPK and AKT downstream signaling pathways and prevent CDDP- and/or CX-induced EGFR nuclear translocation, a well-known mechanism of resistance to chemotherapy. Indeed, VPA impaired the transcription of genes induced by non-canonical activity of nuclear EGFR, such as cyclin D1 and thymidylate synthase. Finally, we confirmed the synergistic antitumor effect also in vivo in both heterotopic and orthotopic models, demonstrating that the combined treatment completely blocked HNSCC xenograft tumors growth in nude mice. Overall, the introduction of a safe and generic drug such as VPA into the conventional treatment for R/M HNSCC represents an innovative and feasible antitumor strategy that warrants further clinical evaluation. A phase II clinical trial exploring the combination of VPA and CDDP/CX in R/M HNSCC patients is currently ongoing in our institute.

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Cetuximab sensitivity of head and neck squamous cell carcinoma xenografts is associated with treatment‐induced reduction in EGFR, pEGFR, and pSrc

Abstract: High sensitivity to cetuximab was strongly associated with a treatment-induced reduction in pEGFR both in vivo and in vitro in a panel of HNSCC cell lines, suggesting that EGFR and pEGFR dynamics could be used as a predictive biomarker for cetuximab treatment response.

Cited by 6 publications

References 21 publications

Hypoxia Mediates Differential Response to Anti-EGFR Therapy in HNSCC Cells

Hypoxia Mediates Differential Response to Anti-EGFR Therapy in HNSCC Cells

The impact of Survivin, WRAP53β, and Hypoxia on treatment response in Head and Neck Cancer

Valproic Acid Synergizes With Cisplatin and Cetuximab in vitro and in vivo in Head and Neck Cancer by Targeting the Mechanisms of Resistance

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