Importance of the field Recent advances in understanding the oncogenesis of head and neck squamous cell carcinomas (HNSCC) have revealed multiple dysregulated signaling pathways. One frequently altered axis is the EGFR/PI3K/Akt/mTOR pathway. This pathway plays a central role in numerous cellular processes including metabolism, cell growth, apoptosis, survival and differentiation, which ultimately contributes to HNSCC progression. What the reader will gain This article reviews the current understanding of EGFR/PI3K/Akt/mTOR signaling in HNSCC, including the impact of both genetic and epigenetic alterations. This review further highlights the potential of targeting this signaling cascade as a promising therapeutic approach in the treatment of HNSCC. Areas covered in this review Books, journals, databases and websites have been searched to provide a current review on the subject. Take home message Genetic alterations of several nodes within this pathway, including both genetic and epigenetic changes, leading to either oncogene activation or inactivation of tumor suppressors, have frequently been implicated in HNSCC. Consequently, drugs that target the central nodes of this pathway have become attractive for molecular oriented cancer therapies. Numerous preclinical and clinical studies are being performed in HNSCC, however, more studies are still needed to better understand the biology of this pathway.

The serine-threonine kinase CK2 exhibits genomic alterations and aberrant overexpression in human head and neck squamous cell carcinomas (HNSCC). Here, we investigated the effects of CK2 inhibitor CX-4945 in human HNSCC cell lines and xenograft models. The IC50's of CX-4945 for 9 UM-SCC cell lines measured by MTT assay ranged from 3.4-11.9 μM. CX-4945 induced cell cycle arrest and cell death measured by DNA flow cytometry, and inhibited prosurvival mediators phospho-AKT and p-S6 in UM-SCC1 and UM-SCC46 cells. CX-4945 decreased NF-κB and Bcl-XL reporter gene activities in both cell lines, but upregulated proapoptotic TP53 and p21 reporter activities, and induced phospho-ERK, AP-1, and IL-8 activity in UM-SCC1 cells. CX-4945 exhibited modest anti-tumor activity in UM-SCC1 xenografts. Tumor immunostaining revealed significant inhibition of PI3K-Akt-mTOR pathway and increased apoptosis marker TUNEL, but also induced p-ERK, c-JUN, JUNB, FOSL1 and proliferation (Ki67) markers, as a possible resistance mechanism. To overcome the drug resistance, we tested MEK inhibitor PD-0325901 (PD-901), which inhibited ERK-AP-1 activation alone and in combination with CX-4945. PD-901 alone displayed significant anti-tumor effects in vivo, and the combination of PD-901 and CX-4945 slightly enhanced anti-tumor activity when compared with PD-901 alone. Immunostaining of tumor specimens after treatment revealed inhibition of p-AKT S129 and p-AKT T308 by CX-4945, and inhibition of p-ERK T202/204 and AP-1 family member FOSL-1 by PD-901. Our study reveals a drug resistance mechanism mediated by the MEK-ERK-AP-1 pathway in HNSCC. MEK inhibitor PD-0325901 is active in HNSCC resistant to CX-4945, meriting further clinical investigation.

PURPOSE A phase I clinical trial and molecular correlative studies were performed to evaluate preclinical evidence for combinatorial activity of proteasome inhibitor bortezomib, epidermal growth factor receptor (EGFR) inhibitor cetuximab, and radiation therapy. EXPERIMENTAL DESIGN Patients with radiotherapy-naïve stage IV or recurrent squamous cell carcinoma of the head and neck (SCCHN) were studied. Escalating doses of bortezomib (0.7, 1.0 and 1.3 mg/m2) were given intravenously twice weekly on days 1, 4, 8, 11, every 21 days, with weekly cetuximab beginning 1 week prior and concurrently with intensity modulated radiotherapy (IMRT), delivered in 2Gy fractions to 70-74 Gy. Molecular effects were examined in serial serum and SCCHN tumor specimens, and the cell line UMSCC-1. RESULTS Seven patients were accrued before the study was terminated when 5/6 previously untreated patients with favorable prognosis oropharyngeal SCCHN progressed within 1 year (PFS =4.8 months; 95% CI, 2.6-6.9). Three patients each received bortezomib 0.7 or 1.0 mg/m2, without dose-limiting toxicities; 1 patient treated at 1.3 mg/m2 was taken off study due to recurring cetuximab infusion reaction and progressive disease. Expected grade 3 toxicities included radiation mucositis (n=4), dermatitis (n=1), and rash (n=1). SCCHN-related cytokines increased in serial serum specimens of patients developing progressive disease (P=0.029). Bortezomib antagonized cetuximab- and radiation-induced cytotoxicity, degradation of EGFR, and enhanced prosurvival signal pathway activation in SCCHN tumor biopsies and UMSCC-1. CONCLUSIONS Combining bortezomib with cetuximab and radiation therapy demonstrated unexpected early progression, evidence for EGFR stabilization, increased prosurvival signaling and SCCHN cytokine expression, warranting avoidance of this combination.