Modeling the transcriptional consequences of epidermal growth factor receptor ablation in Ras-initiated squamous cancer.

ABSTRACT: PURPOSE:Epidermal growth factor receptor (EGFR)-targeted therapy is in clinical use to treat squamous cell carcinoma of the head and neck and other cancers of lining epithelium. RAS mutations in these tumors are a negative prognostic factor for response, and skin inflammation is an adverse reaction to therapy. We investigated transcriptional and biochemical changes that could account for the confounding effects of RAS activation and inflammation in a squamous tissue. EXPERIMENTAL DESIGN:We carried out gene expression profiling on oncogenic Ras-transformed and wild-type mouse and human keratinocytes with EGFR ablated chronically by genetic deletion or acutely by drug treatment and followed leads provided by pathway analysis with biochemical studies. RESULTS:We identified a 25-gene signature specific to the Ras-EGFR ablation interaction and a distinct 19-gene EGFR ablation signature on normal keratinocytes. EGFR ablation in the context of wild-type Ras reduces ontologies favoring cell-cycle control and transcription, whereas oncogenic Ras enriches ontologies for ion channels and membrane transporters, particularly focused on calcium homeostasis. Ontologies between chronic EGFR ablation and acute pharmacologic ablation were unique, both with and without Ras activation. p38? is activated in response to abrogation of EGFR signaling under conditions of Ras activation in both mouse and human keratinocytes and in RAS-transformed tumor orthografts of EGFR-ablated mouse keratinocytes. EGFR ablation in the absence of oncogenic Ras revealed Erk and interleukin-1?-related pathways. CONCLUSION:These findings reveal unrecognized interactions between Ras and EGFR signaling in squamous tumor cells that could influence the therapeutic response to EGFR ablation therapy.

SUBMITTER: Wright LN 

PROVIDER: S-EPMC3251736 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature