Effect of erlotinib on epidermal growth factor receptor and downstream signaling in oral cavity squamous cell carcinoma

Abstract

Purpose To determine if there are differences in biomarker modulation and EGFR degradation between tumor and the normal mucosa following treatment with an EGFR inhibitor, erlotinib, in head and neck cancer. Methods Patients with primary oral cavity squamous cell cancers received a course of erlotinib, 150 mg qd for 7 days prior to surgical resection. Tumor and normal mucosa biopsies were obtained both pre and post erlotinib. Changes in known markers of EGFR activity (phospho, AKT, STAT3) were measured by immunoblotting, while changes in tissue distribution were analyzed by immunohistochemical analysis. Results Twelve patients were enrolled; seven had evaluable paired tumor and normal mucosa biopsies pre and post treatment. Expression of EGFR was higher in tumor compared to the normal mucosa (p=0.005). Erlotinib administration was associated with marked inhibition of pEGFR and reduction in total EGFR protein (p=0.004, p=0.007) in tumors while there was heterogeneity in EGFR inhibition in the normal mucosa (p=0.1 (pEGFR), and p=0.07 (EGFR). Reduced levels of pSrc and pSTAT3 and enhanced p27 levels were noted in tumors following erlotinib. Cell culture studies confirmed that EGFR is degraded in tumor cells after prolonged treatment with erlotinib. Conclusion Our results show that EGFR inhibition by erlotinib led to a marked reduction in EGFR protein levels in patients. Differential effects of erlotinib on tumor compared to the normal mucosa suggest there may be individual patient heterogeneity. These preliminary data suggest EGFR degradation should be further analyzed as a potential biomarker in selecting patients likely to benefit from EFGR inhibitors.

Randomized, placebo-controlled window trial of EGFR, Src, or combined blockade in head and neck cancer

“…Assessment of each autophosphorylation site is limited by the quality of available antisera, particularly for IHC analyses. As measured by immunoblotting, expression of pEGFR on a nonautophosphorylation site, pY845, was reportedly decreased in 7 HNSCC patients treated with 7 days of erlotinib on a window trial (29). Curiously, pY845 has been previously associated with Src signaling (30).…”

Role of Stat3 in Skin Carcinogenesis: Insights Gained from Relevant Mouse Models

“…In this regard, inhibiting EGFR-Stat3 pathway in 4-nitroquinoline-1-oxide (4-NQO-) induced murine model of oral carcinogenesis by erlotinib, a small molecule inhibitor of EGFR, inhibited development of preneoplastic lesions and oral tumors by approximately 70% with a concomitant decrease of Stat3 levels in erlotinib-treated mice [56]. Similarly, primary human oral cavity squamous cell cancers showed reduced levels of both EGFR and p-Stat3 after treatment with erlotinib compared to pretreated paired tissue [57]. Moreover, combined molecular targeting of Stat3 sensitizes cells to radiotherapy and small molecule chemotherapeutic agents in vitro [58, 59].…”

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

“…Studies have shown an increase in overall survival of almost 20 months in HNSCC patients who received targeted therapy against EGFR in combination with radiotherapy compared to radiotherapy alone . At the same time, only a subset of HNSCC patients receiving cetuximab actually respond to treatment, underlining the need for a means to tailor treatments to individual patients .…”