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Induction of anaplastic lymphoma kinase (ALK) as a novel mechanism of EGFR inhibitor resistance in head and neck squamous cell carcinoma patient-derived models.
Abstract Head and neck squamous cell carcinoma (HNSCC) currently only has one FDA-approved cancer intrinsic targeted therapy, the epidermal growth factor receptor (EGFR) inhibitor cetuximab, to which only approximately 10% of tumors are sensitive. In order to extend therapy options, we subjected patient-derived HNSCC cells to small-molecule inhibitor and siRNA screens, first, to find effective combination therapies with an EGFR inhibitor, and second, to determine a potential mechanistic basis for repurposing the FDA approved agents for HNSCC. The combinations of EGFR inhibitor with anaplastic lymphoma kinase (ALK)...
Source: Cancer Biology and Therapy - June 1, 2018 Category: Cancer & Oncology Authors: Ouyang X, Barling A, Lesch A, Tyner JW, Choonoo G, Zheng C, Jeng S, West TM, Clayburgh D, Courtneidge SA, McWeeney SK, Kulesz-Martin M Tags: Cancer Biol Ther Source Type: research

Combination of cetuximab with met inhibitor in control of cetuximab-resistant oral squamous cell carcinoma.
Conclusions: This study demonstrates that Met/HGF expression results in OSCC resistance to cetuximab and tumor recurrence after cetuximab therapy; thus, inhibition of Met/HGF activity could restore OSCC sensitivity to cetuximab. PMID: 31105843 [PubMed]
Source: American Journal of Translational Research - May 22, 2019 Category: Research Tags: Am J Transl Res Source Type: research

Acquired resistance to cetuximab is associated with the overexpression of Ras family members and the loss of radiosensitization in head and neck cancer cells
Conclusion: Targeting Ras and PI3K activity improves the outcome of irradiation in cetuximab-resistant HNSCC cell lines in vitro.
Source: Radiotherapy and Oncology - July 29, 2013 Category: Radiology Authors: Mohammad Saki, Mahmoud Toulany, H. Peter Rodemann Tags: Original Articles Source Type: research

Abstract LB-215: The TAM family of receptor tyrosine kinases play a role in acquired resistance to cetuximab
Cetuximab is an anti-epidermal growth factor receptor (EGFR) monoclonal antibody that has shown efficacy in metastatic colorectal cancer, head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC). Clinical data suggests that patients whom initially respond to cetuximab eventually acquire resistance, highlighting the importance of understanding resistant mechanisms for the development of better treatment regimes for cancer patients. Recent studies have identified a role for the TAM family of receptor tyrosine kinases (Tyro, Axl, and Mer) in tumor biology, and more specifically the Axl receptor as ...
Source: Cancer Research - September 30, 2014 Category: Cancer & Oncology Authors: Brand, T. M., Iida, M., Corrigan, K. L., Luthar, N., Hornung, M., Toulany, M., Gill, P., Salgia, R., Wheeler, D. L. Tags: Experimental and Molecular Therapeutics Source Type: research

Targeting of the EGFR/β1 integrin connecting proteins PINCH1 and Nck2 radiosensitizes three-dimensional SCC cell cultures.
Authors: Rossow L, Eke I, Dickreuter E, Cordes N Abstract Epidermal growth factor receptor (EGFR) signaling plays an important role in tumor cell resistance to therapy. In addition to ligand binding, mutual and cooperative interactions of EGFR with integrin cell adhesion receptors critically influence proper downstream signaling through a number of bridging adapter proteins. In the present study, we analyzed the role of two of these adapter proteins, called PINCH1 and Nck2, for cellular radioresistance in combination with EGFR-targeting using the monoclonal antibody cetuximab. siRNA-mediated knockdown of PINCH1 or ...
Source: Oncology Reports - May 28, 2015 Category: Cancer & Oncology Tags: Oncol Rep Source Type: research

STAT1 and Cisplatin/Cetuximab in HNSCC
Cisplatin is a cytotoxic chemotherapeutic drug frequently used to treat many solid tumors, including head and neck squamous cell carcinoma (HNSCC). EGF receptor (EGFR) inhibitors have also shown efficacy as alternatives to cisplatin in some situations. However, large clinical trials have shown no added survival benefit from the use of these two drugs in combination. Possible explanations for this include overlapping downstream signaling cascades. Using in vitro studies, we tested the hypothesis that cisplatin and EGFR inhibitors rely on the activation of the tumor suppressor STAT1, characterized by its phosphorylation at s...
Source: Molecular Cancer Therapeutics - September 2, 2015 Category: Cancer & Oncology Authors: Schmitt, N. C., Trivedi, S., Ferris, R. L. Tags: Cancer Biology and Signal Transduction Source Type: research

The FA/BRCA Pathway Identified as the Major Predictor of Cisplatin Response in Head and Neck Cancer by Functional Genomics
Patients with advanced stage head and neck squamous cell carcinoma (HNSCC) are often treated with cisplatin-containing chemoradiation protocols. Although cisplatin is an effective radiation sensitizer, it causes severe toxicity and not all patients benefit from the combination treatment. HNSCCs expectedly not responding to cisplatin may better be treated with surgery and postoperative radiation or cetuximab and radiation, but biomarkers to personalize chemoradiotherapy are not available. We performed an unbiased genome-wide functional genetic screen in vitro to identify genes that influence the response to cisplatin in HNS...
Source: Molecular Cancer Therapeutics - March 1, 2017 Category: Cancer & Oncology Authors: Martens-de Kemp, S. R., Brink, A., van der Meulen, I. H., de Menezes, R. X., te Beest, D. E., Leemans, C. R., van Beusechem, V. W., Braakhuis, B. J. M., Brakenhoff, R. H. Tags: Companion Diagnostics and Cancer Biomarkers Source Type: research

Molecular mechanisms of apoptosis and autophagy elicited by combined treatment with oridonin and cetuximab in laryngeal squamous cell carcinoma
AbstractCombined oridonin (ORI), a natural and safe kaurene diterpenoid isolated fromRabdosia rubescens, and cetuximab (Cet), an anti-EGFR monoclonal antibody, have been reported to exert synergistic anti-tumor effects against laryngeal squamous cell carcinoma (LSCC) both in vitro and in vivo by our group. In the present study, we further found that ORI/Cet treatment not only resulted in apoptosis but also induced autophagy. AMPK/mTOR signaling pathway was found to be involved in the activation of autophagy in ORI/Cet-treated LSCC cells, which is independent of p53 status. Additionally, chromatin immunoprecipitation (ChIP)...
Source: Apoptosis - November 14, 2018 Category: Molecular Biology Source Type: research