Inhibition of EGFR-STAT3 Signaling with Erlotinib Prevents Carcinogenesis in a Chemically-Induced Mouse Model of Oral Squamous Cell Carcinoma

Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Cancer Prevention Research (Impact Factor: 4.44). 02/2011; 4(2):230-7. DOI: 10.1158/1940-6207.CAPR-10-0249
Source: PubMed


Chemoprevention of head and neck squamous cell carcinoma (HNSCC), a disease associated with high mortality rates and frequent occurrence of second primary tumor (SPT), is an important clinical goal. The epidermal growth factor receptor (EGFR)-signal transducer and activator of transcription (STAT)-3 signaling pathway is known to play a key role in HNSCC growth, survival, and prognosis, thereby serving as a potential therapeutic target in the treatment of HNSCC. In the current study, the 4-nitroquinoline-1-oxide (4-NQO)-induced murine model of oral carcinogenesis was utilized to investigate the chemopreventive activities of compounds that target the EGFR-STAT3 signaling pathway. This model mimics the process of oral carcinogenesis in humans. The drugs under investigation included erlotinib, a small molecule inhibitor of the EGFR, and guggulipid, the extract of an Ayurvedic medicinal plant, which contains guggulsterone, a compound known to inhibit STAT3. Dietary administration of guggulipid failed to confer protection against oral carcinogenesis. On the other hand, the mice placed on erlotinib-supplemented diet exhibited a 69% decrease (P < 0.001) in incidence of preneoplastic and neoplastic lesions compared with mice on the control diet. Immunostaining of dysplastic lesions demonstrated modest decreases in STAT3 levels, with both drug treatments, that were not statistically significant. The results of the present study provide the basis for exploring the efficacy of erlotinib for prevention of HNSCC in a clinical setting.

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    • "In addition, reducing Stat3 activity by targeting upstream proteins has shown promise in HNSCC preclinical and clinical studies. 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]. "
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    ABSTRACT: Signal transducer and activator of transcription 3 (Stat3) is a cytoplasmic protein that is activated in response to cytokines and growth factors and acts as a transcription factor. Stat3 plays critical roles in various biological activities including cell proliferation, migration, and survival. Studies using keratinocyte-specific Stat3-deficient mice have revealed that Stat3 plays an important role in skin homeostasis including keratinocyte migration, wound healing, and hair follicle growth. Use of both constitutive and inducible keratinocyte-specific Stat3-deficient mouse models has demonstrated that Stat3 is required for both the initiation and promotion stages of multistage skin carcinogenesis. Further studies using a transgenic mouse model with a gain of function mutant of Stat3 (Stat3C) expressed in the basal layer of the epidermis revealed a novel role for Stat3 in skin tumor progression. Studies using similar Stat3-deficient and gain-of-function mouse models have indicated its similar roles in ultraviolet B (UVB) radiation-mediated skin carcinogenesis. This paper summarizes the use of these various mouse models for studying the role and underlying mechanisms for the function of Stat3 in skin carcinogenesis. Given its significant role throughout the skin carcinogenesis process, Stat3 is an attractive target for skin cancer prevention and treatment.
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    • "These observations support the evidence that inhibition of head and neck cutaneous squamous cell carcinoma cell invasion by GSPs is mediated through their inhibitory effects on EGFR expression. It has been reported that inhibitors of EGFR can prevent the growth and progression of HNSCC; however, long term use may also induce some form of toxicity [19,20]. This possibility is not expected with the use of GSPs as these are dietary components and toxicity has not been observed in animal models [11,12]. "
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    Full-text · Article · Dec 2011 · BMC Complementary and Alternative Medicine
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