Loss of p120ctn causes EGFR-targeted therapy resistance and failure

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.

Black raspberry restores the expression of the tumor suppressor p120ctn in the oral cavity of mice treated with the carcinogen dibenzo[a,l]pyrene diol epoxide

“…In mice treated with DBPDE we found that diet containing 5% BRB resulted in a significant reduction of tumor formation [ 15 ]. Given that p120ctn can alter EGFR therapy in HNSCC [ 10 ] and, as shown in Fig 1 , p120ctn is downregulated following DBPDE treatment, we set out to determine if BRB treatment altered p120ctn expression in DBPDE-induced tumors. Oral cavity tissue was previously harvested from DBPDE treated mice with and without BRB administration.…”

“…Because we have previously shown that decreased p120ctn expression causes EGFR therapy resistance [ 10 ], we wanted to determine EGFR expression levels in DBPDE treated tumors and whether BRB treatment altered its expression. In normal epithelium, EGFR is strongly expressed in the basal layers, and expression decreases as the epithelium differentiates and migrates toward the superficial layers ( Fig 6A ).…”

“…Specifically, following BRB administration the expression of important oncoproteins such as EGFR and NFkB were significantly reduced. We have shown previously that decreased expression of p120ctn can cooperate with EGFR to promote carcinogenesis and can cause EFGR therapy failure [ 10 ]. In the present studies we showed that BRB significantly increased p120ctn expression in mice treated with DBPDE.…”

“…Thus, p120ctn loss is not only important as a marker of a poor prognosis in oral cancer, it is also a major driver of the carcinogenic process. Relevant to HNSCC therapy, loss of p120ctn also induces resistance to Cetuximab, a targeted EGFR therapy frequently used to treat local-regional HNSCC [ 10 ].…”

Noninvasive Evaluation of EGFR Expression of Digestive Tumors Using 99mTc-MAG3-Cet-F(ab′)2-Based SPECT/CT Imaging

“…EGFR is widely expressed in nearly every cancer type, and its high expression in tumors correlates with poor patient out-come [16]. Several studies have demonstrated that patients with digestive tumors benefited from EGFR-targeted therapy using cetuximab [17][18][19].…”