Background
The purpose of this study was to identify mechanisms of innate resistance to an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, erlotinib, in a panel of head and neck squamous cell carcinoma (HNSCC) cell lines. Specifically, we analyzed the role of HRAS mutations in erlotinib resistance.

Methods
Erlotinib sensitivity was determined by methyl thiazolyl-tetrazolium (MTT) assays. Molecular signaling pathways and somatic mutations were examined. Changes in sensitivity after modulation of HRAS expression were evaluated.

Results
All 7 cell lines were wild-type for EGFR and KRAS regardless of erlotinib sensitivity; however, 1 erlotinib-resistant cell line (HN31) harbored an HRAS G12D mutation. Downregulation of HRAS expression by small interfering RNA (siRNA) or short hairpin RNA (shRNA) in HN31 led to increased erlotinib sensitivity in vitro and in vivo. Transfection of activating HRAS-mutant (G12D and G12V) constructs into erlotinib-sensitive cell lines made them more resistant to erlotinib.

Conclusion
Activating HRAS mutations can confer erlotinib resistance in an HRAS mutant HNSCC cell line. © 2014 Wiley Periodicals, Inc. Head Neck 36: 1547–1554, 2014

/pdf/hras-mutations-and-resistance-to-the-epidermal-growth-factor-235jmv8xgr.pdf

HRAS mutations and resistance to the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in head and neck squamous cell carcinoma cells

The epidermal growth factor receptor (EGFR) is overexpressed in the vast majority of cases of squamous cell carcinoma of the head and neck (SCCHN). A high EGFR expression is associated with an unfavorable prognosis. Cetuximab is a chimeric human/murine IgG1 antibody which binds with high affinity to the EGFR. It is the only targeted agent which got approval for the treatment of SCCHN from the regulatory agencies of Europe and the United States, both in locoregionally advanced disease, in association with radiation, and in recurrent/metastatic disease. The outcome of trials involving other EGFR-directed monoclonal antibodies, that is, zalutumumab and panitumumab, was consistent with the results with cetuximab. However these trials failed to meet their primary endpoint. The results with EGFR-directed tyrosine kinase inhibitors have been disappointing. Other potential targets for treatment in SCCHN include the entire ErbB family, the vascular endothelial growth factor (VEGF) and its receptor (VEGFR), the insulin-like growth factor 1 receptor (IGF-1R), the insulin receptor (IR), histone deacetylases (HDAC), the mammalian target of rapamycin (mTOR), the platelet-derived growth factor receptor (PDGFR), heat-shock protein 90 (HSP90), nuclear factor-kappa B (NF-κB), aurora A or B, and phosphatidylinositol 3-kinase (PIK3CA).

/pdf/biologic-therapy-in-head-and-neck-cancer-a-road-with-hurdles-513xkmbsa3.pdf

Biologic Therapy in Head and Neck Cancer: A Road with Hurdles

Lessons learned The combination of cisplatin, docetaxel, and erlotinib as frontline treatment for recurrent and/or metastatic head and neck squamous cell carcinomas led to a response rate of 62%.This result exceeded the prespecified target response rate of 50% and represented an improvement compared with historical controls.This regimen warrants further investigation. Background The epidermal growth factor receptor (EGFR) plays a key role in the carcinogenesis of head and neck squamous cell carcinomas (HNSCC). We conducted this clinical study to test the hypothesis that the addition of erlotinib to first-line cisplatin and docetaxel for patients with recurrent and/or metastatic HNSCC would yield a response rate of at least 50%, representing an improvement from historical controls. Methods Patients with recurrent and/or metastatic HNSCC, with at least one measurable lesion, no prior chemotherapy for recurrent and/or metastatic disease, prior combined modality therapy completed >6 months before enrollment, and performance status ≤2 were treated with cisplatin, docetaxel, and erlotinib for up to six cycles, followed by maintenance erlotinib until disease progression. The primary endpoint was response rate. Results Fifty patients were enrolled (42 male, 12 never smokers, 19 with oropharynx cancer). The median number of cycles was five; 31 patients initiated maintenance erlotinib; 14 patients required erlotinib dose reductions. The objective response rate was 62%, and the median progression-free and overall survival were 6.1 and 11.0 months, respectively. Toxicity profiles were consistent with the known side effects of the study drugs. Conclusion The study met its primary endpoint and improved response rates compared with historical controls. The findings support further evaluation of the regimen for recurrent and/or metastatic HNSCCs.

Single Arm, Phase II Study of Cisplatin, Docetaxel, and Erlotinib in Patients with Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinomas

New data integrating multitargeted antifolates into treatment of first-line and relapsed non-small-cell lung cancer.

Pemetrexed in head and neck cancer: A systematic review

5520 Background: In EGFR over expressing cell lines, higher doses of erlotinib block downstream signaling more effectively (e.g., MAPK) than lower doses, despite a similar degree of EGFR phosphoryl...

Randomized trial of a short course of erlotinib 150 to 300 mg daily prior to surgery for squamous cell carcinomas of the head and neck (SCCHN) in current, former, and never smokers: Objective responses and clinical outcomes.

6055 Background: Despite recent advances in therapy, patients (pts) with recurrent or metastatic HNSCC continue to demonstrate a poor median survival. In these pts, early trials with pemetrexed, a ...

A phase I dose escalation study of pemetrexed in patients with advanced head and neck squamous cell cancer (HNSCC)

e17009 Background: Pemetrexed is a novel antimetabolite that inhibits both purine and pyrimidine biosynthesis. Because its mechanism of action is similar to that of both methotrexate and 5-FU, it m...

Phase I study of pemetrexed in recurrent/metastatic head and neck squamous cell cancer (HNSCC) and to assess the need for steroid premedication

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Randomized trial of a short course of erlotinib 150 to 300 mg daily prior to surgery for squamous cell carcinomas of the head and neck (SCCHN) in current, former, and never smokers: Objective responses and clinical outcomes.

A phase I dose escalation study of pemetrexed in patients with advanced head and neck squamous cell cancer (HNSCC)

Phase I study of pemetrexed in recurrent/metastatic head and neck squamous cell cancer (HNSCC) and to assess the need for steroid premedication