New Strategies in Head and Neck Cancer: Understanding Resistance to Epidermal Growth Factor Receptor Inhibitors

Chen, Lucy F.; Cohen, Ezra E.W.; Grandis, Jennifer R.

doi:10.1158/1078-0432.ccr-09-2318

Cited by 105 publications

(88 citation statements)

References 56 publications

(66 reference statements)

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“…This is in accordance with reports in the literature on the development of resistance to TKIs in HNSCC in which tyrosine kinase mutations of Egfr are rare events. 28 Cancer cells become resistant to EGFR targeted therapies through several mechanisms. The nature of the gefitinib resistance in the SCCF1G cell line in this study is not known, but some of the previously reported mechanisms of resistance could be consistent with an apparent resistance to tyrosine kinase inhibition but not to siRNA.…”

Section: Discussionmentioning

confidence: 99%

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Studies on the inhibition of feline EGFR in squamous cell carcinoma: Enhancement of radiosensitivity and rescue of resistance to small molecule inhibitors

Bergkvist¹,

Argyle²,

Pang³

et al. 2011

Cancer Biology & Therapy

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Section: Discussionmentioning

confidence: 99%

“…Acquired resistance to TKI monotherapy commonly develops over time, 28 so a gefitinib resistant cell line (SCCF1G) was developed and the tyrosine kinase region was re-sequenced, but no mutations were found. Using proliferation assays, the SCCF1G cell line showed no significant inhibition of proliferation at the 5 μM drug dose (Fig.…”

Section: Introductionmentioning

confidence: 99%

Studies on the inhibition of feline EGFR in squamous cell carcinoma: Enhancement of radiosensitivity and rescue of resistance to small molecule inhibitors

Bergkvist¹,

Argyle²,

Pang³

et al. 2011

Cancer Biology & Therapy

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“…[33][34][35][36] Cal 33 microtumors that were harvested from 300-mm PEGDMA hydrogel microarray devices after 4 days in culture were treated -EGF (50 ng/mL) for 15 min and fixed in paraformaldehyde and stained with Hoechst. The fixed microtumors were then permeabilized in 95% ice-cold methanol, and then the total ERK1/2 or phopspho-ERK1/2 expression levels were determined by indirect immunofluorescence antibody staining, image acquisition on the IXM, and image analysis using the MWCS module (Fig.…”

Section: Activation and Inhibition Of Egf Pathway Activation In Cal 3mentioning

confidence: 99%

Production of Uniform 3D Microtumors in Hydrogel Microwell Arrays for Measurement of Viability, Morphology, and Signaling Pathway Activation

Singh

Mukundan

et al. 2015

ASSAY and Drug Development Technologies

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Despite significant investments in cancer research and drug discovery/development, the rate of new cancer drug approval is £5% and most cases of metastatic cancer remain incurable. Ninety-five percent of new cancer drugs fail in clinical development because of a lack of therapeutic efficacy and/or unacceptable toxicity. One of the major factors responsible for the low success rate of anticancer drug development is the failure of preclinical models to adequately recapitulate the complexity and heterogeneity of human cancer. For throughput and capacity reasons, high-throughput screening growth inhibition assays almost exclusively use two-dimensional (2D) monolayers of tumor cell lines cultured on tissue culture-treated plastic/glass surfaces in serum-containing medium. However, these 2D tumor cell line cultures fail to recapitulate the three-dimensional (3D) context of cells in solid tumors even though the tumor microenvironment has been shown to have a profound effect on anticancer drug responses. Tumor spheroids remain the best characterized and most widely used 3D models; however, spheroid sizes tend to be nonuniform, making them unsuitable for high-throughput drug testing. To circumvent this challenge, we have developed defined size microwell arrays using nonadhesive hydrogels that are applicable to a wide variety of cancer cell lines to fabricate sizecontrolled 3D microtumors. We demonstrate that the hydrogel microwell array platform can be applied successfully to generate hundreds of uniform microtumors within 3-6 days from many cervical and breast, as well as head and neck squamous cell carcinoma (HNSCC) cells. Moreover, controlling size of the microwells in the hydrogel array allows precise control over the size of the microtumors. Finally, we demonstrate the application of this platform technology to probe activation as well as inhibition of epidermal growth factor receptor (EGFR) signaling in 3D HNSCC microtumors in response to EGF and cetuximab treatments, respectively. We believe that the ability to generate large numbers of HNSCC microtumors of uniform size and 3D morphology using hydrogel arrays will provide more physiological in vitro 3D tumor models to investigate how tumor size influences signaling pathway activation and cancer drug efficacy.

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“…These fall into two categories. First, resistance may develop via constitutive activation of growth caused by changes in effectors of the EGFR signal transduction pathway (23)(24)(25)(26). Second, proliferation may be stimulated by activation of receptors other than EGFR (27)(28)(29)(30).…”

Section: Introductionmentioning

confidence: 99%

Resistance of oral squamous cell carcinoma cells to cetuximab is associated with EGFR insensitivity and enhanced stem cell-like potency

et al. 2014

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Abstract. Cetuximab, a specific anti-epidermal growth factor receptor (EGFR) monoclonal antibody, is used in cancer treatment. Although development of resistance to cetuximab is well recognized, the underlying mechanisms remain unclear.In the present study, we characterized cetuximab-resistant oral squamous cell carcinoma (OSCC) cell lines. The human OSCC cell lines HSC3, HSC4 and SAS were used in the present study. Effects of inhibitors including cetuximab on growth in cells were assessed by MTT assays. Southern blotting and immunofluorescence analysis were performed to examine protein expression and localization. Sphere formation was used to characterize stem cell-like properties. Floating aggregation culture was used for anchorage-independent growth. Cetuximab inhibited proliferation of HSC3 and HSC4 cells, but not SAS cells. Proliferation of all three cell lines was inhibited by the EGFR/ErbB2/ErbB4 inhibitor II. The EGFR inhibitor AG1478 strongly inhibited HSC3 and HSC4 proliferation, but that of SAS cells only moderately. EGFR proteins were localized on cell surface and phosphorylated in all three cell lines. SAS cells could proliferate in serum-free monolayer culture and formed spheres from single cells in floating culture. HSC3 and HSC4 could not proliferate under serum-free culture conditions and could not form spheres. Growth of SAS spheres required serum, and was inhibited by both AG1478 and cetuximab. Thus, cetuximab-resistant SAS cells not only engaged in EGFR-independent growth but also exhibited stem cell-like properties. However, growth was EGFR-dependent in aggregation culture, and the SAS cell aggregates became cetuximab-sensitive. This suggests that cetuximab sensitivity is not only cell-type-dependent but is also affected by the growth microenvironment.

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New Strategies in Head and Neck Cancer: Understanding Resistance to Epidermal Growth Factor Receptor Inhibitors

Cited by 105 publications

References 56 publications

Studies on the inhibition of feline EGFR in squamous cell carcinoma: Enhancement of radiosensitivity and rescue of resistance to small molecule inhibitors

Studies on the inhibition of feline EGFR in squamous cell carcinoma: Enhancement of radiosensitivity and rescue of resistance to small molecule inhibitors

Production of Uniform 3D Microtumors in Hydrogel Microwell Arrays for Measurement of Viability, Morphology, and Signaling Pathway Activation

Resistance of oral squamous cell carcinoma cells to cetuximab is associated with EGFR insensitivity and enhanced stem cell-like potency

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