Abstract
Epidermal growth factor receptor (EGFR) plays a vital role in cell division and survival signaling pathways. EGFR is activated in nearly every cancer type, and its high expression in tumors is correlated with poor patient outcome. Altogether, EGFR is a prime candidate as a therapeutic target. While targeted EGFR therapy is initially effective in 75% of patients, a majority of patients relapse within the first year due to poorly understood mechanisms of resistance. p120-catenin (p120ctn) has recently been implicated as a biomarker for EGFR therapy. In previous studies, we demonstrated that p120ctn is a tumor suppressor and its loss is capable of inducing cancer. Furthermore, p120ctn down-regulation synergizes with EGFR overexpression to cause a highly invasive cell phenotype. The purpose of this present study was to investigate whether p120ctn down-regulation induced EGFR therapeutic resistance. Using human esophageal keratinocytes, we have found that EGFR-targeting compounds are toxic to cells overexpressing EGFR. Interestingly, these therapies do not cause toxicity in cells with EGFR overexpression and decreased p120ctn expression. These data suggest that decreased p120ctn causes resistance to EGFR therapy. We believe these findings are of utmost importance, as there is an unmet need to discover mechanisms of EGFR resistance.
Highlights
Epidermal growth factor receptor (EGFR) mediates intracellular signaling pathways that regulate cell proliferation and survival [1, 2]
There is a crucial need to identify and understand these resistance mechanisms and identify the genes and mutations that can modify the effectiveness of EGFR therapy
We demonstrated that p120ctn down-regulation intersects and synergizes with EGFR overexpression to induce an aggressive and invasive cancer phenotype [31]
Summary
Epidermal growth factor receptor (EGFR) mediates intracellular signaling pathways that regulate cell proliferation and survival [1, 2]. It is activated in many types of epithelial cancers, including head and neck, esophageal, lung, liver, pancreatic, colon, skin, and bladder [2, 3]. EGFR is over-activated by mutation, amplification, or overexpression, and high levels of EGFR in tumors and metastases is correlated with poorer patient outcome [2]. This makes it an ideal candidate for targeted therapies.
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