EGFR Signaling In Cancer Research Articles

The story of EGFR: from signaling pathways to a potent anticancer target.

EGFR is a member of the ERBB family. It plays a significant role in cellular processes such as growth, survival and differentiation via the activation of various signaling pathways. EGFR deregulation is implicated in various human malignancies, and therefore EGFR has emerged as an attractive anticancer target. EGFR inhibition using strategies such as tyrosine kinase inhibitors and monoclonal antibodies hinders cellular proliferation and promotes apoptosis in cancer cells in vitro and in vivo. EGFR inhibition by tyrosine kinase inhibitors has been shown to be a better treatment option than chemotherapy for advanced-stage EGFR-driven non-small-cell lung cancer, yet de novo and acquired resistance limits the clinical benefit of these therapeutic molecules. This review discusses the cellular signaling pathways activated by EGFR. Further, current therapeutic strategies to target aberrant EGFR signaling in cancer and mechanisms of resistance to them are highlighted.

LGR4: Not Just for Wnt Anymore?

Leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) is best known for its role in regulating the ability of cells to respond to Wnt ligands. In this well-known role, LGR4 serves as a receptor for R-spondins and forms a complex with the ubiquitin E3 ligases ring finger protein 43 (RNF43) and zinc and ring finger 3 (ZNRF3). RNF43 and ZNRF3 ubiquitinate Frizzleds (FZD), which are a family of ten WNT receptors. This ubiquitination decreases FZD receptor levels on the cell surface, reducing Wnt ligands' ability to activate signaling. While there were some previous indications of Wnt-independent functions of LGR4, this WNT-centric view has remained predominant. In this issue of Cancer Research, Yue and colleagues report that LGR4 also functions to regulate signaling through the EGF receptor. This work was stimulated by observing that while high levels of LGR4 expression in breast tumors correlated with poor patient outcomes, LGR4 levels did not correlate with a well-established Wnt-associated gene signature in these same patients. In contrast, high levels of Lgr4 expression strongly correlated with EGFR signaling. Reducing Lgr4 expression also inhibited signaling through the EGFR, potentially via regulation of the Casitas B-lineage lymphoma ubiquitin E3 ligase. Consistent with this model, LGR4 could be coimmunoprecipitated with a complex that contained EGFR and was capable of inhibiting EGFR ubiquitination. The implications of this work and how it challenges our understanding of the contributions of Wnt signaling and EGFR signaling in cancer are discussed as our several interesting future directions.See related article by Yue et al., p. 4441.

Cytokine stimulation of MUC4 expression in human female reproductive tissue carcinoma cell lines and endometrial cancer.

MUC4, a transmembrane glycoprotein, interferes with cell adhesion, and promotes EGFR signaling in cancer. Studies in rat models have demonstrated steroid hormonal regulation of endometrial MUC4 expression. In this study, qRT-PCR screening of mouse tissues determined that Muc4 mRNA also was robustly expressed in mouse uteri. Previous studies from our labs have demonstrated MUC4 mRNA was expressed at levels <1% of MUC1 mRNA in human endometrium and endometriotic tissue. Multiple human endometrial adenocarcinoma cell lines were assayed for MUC4 mRNA expression revealing extremely low basal expression in the Ishikawa, RL-95-2, AN3CA, and KLE lines. Moderate to high expression was observed in HEC50 and HEC-1A cells. MUC4 mRNA expression was not affected by progesterone and/or estrogen treatment, but was greatly stimulated at both mRNA and protein levels by proinflammatory cytokines (IFN-γ and TNF-α), particularly when used in combination. In endometrial tissue, MUC4 mRNA levels did not change significantly between normal or cancerous samples; although, a subset of patients with grade 1 and 2 tumors displayed substantially higher expression. Likewise, immunostaining of human endometrial adenocarcinoma tissues revealed little to no staining in many patients (low MUC4), but strong staining in some patients (high MUC4) independent of cancer grade. In cases where staining was observed, it was heterogeneous with some cells displaying robust MUC4 expression and others displaying little or no staining. Collectively, these observations demonstrate that while MUC4 is highly expressed in the mouse uterus, it is not a major mucin in normal human endometrium. Rather, MUC4 is a potential marker of endometrial adenocarcinoma in a subset of patients.

Abstract 5209: Abrogation of STAT3 activation by JSI-124 enhances dasatinib-induced cytotoxicity in malignant human glioma cell lines

Abstract Src family kinases (SFK) collectively regulate a variety of cellular functions in many cancer types including proliferation, invasion, motility, survival, differentiation, and angiogenesis. Src greatly enhances EGFR-mediated transformation, raising the possibility that Src and/or its related family members may be effectors of EGFR signaling in cancer, including in glioblastoma. Although Dasatinib (BMS-354825), an ATP-competitive, small molecule tyrosine kinase inhibitor, suppresses the activity of SFKs at nanomolar concentrations, IC50 values ranged from 7 to 30 µM for inhibition of proliferation, well above the clinically achievable range. Because Src kinases were initially implicated in STAT activation, we hypothesized that the combination of Src inhibitor dasatinib and JAK2/STAT3 inhibitor JSI-124 would promote glioma cytotoxicity by decreasing both the activation status of c-Src and STAT3, as well as downregulating the levels of other relevant signaling effectors. We, therefore, examined the effects of dasatinib and JSI-124, alone or in combination, on signal transduction, migration and apoptosis in a series of malignant human glioma cell lines. JSI-124 significantly enhanced the efficacy of dasatinib in vitro. Combination of dasatinib and JSI-124 displayed a significant inhibition of cell migration in all cell lines. The effects on cell migration correlated with the inhibition of Src and downstream mediators of adhesion (e.g. focal adhesion kinase). Cells exposed to dasatinib and JSI-124 induced morphological changes that were consistent with an upstream role for Src in regulating focal adhesion complexes. Taken together, targeting Src and STAT pathway may contribute to the treatment of cancers that demonstrate increased levels of EGFR, Src and STATs, including malignant human glioma Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5209.

Convergence between Wnt-β-catenin and EGFR signaling in cancer

Wnt and EGFR signaling play key roles in embryonic development and cell proliferation. It is well documented that dysregulation of these two pathways often leads to tumorigenesis with poor prognosis. However, the possible crosstalk between the two pathways in cancer development is largely unknown. Although some reports show that EGFR might antagonize Wnt signaling during development in Drosophila, an increasing body of evidence indicates that Wnt and EGFR signaling crosstalk and transactivate one another in development and cancer. This review summarizes recent studies on the crosstalk between Wnt and EGFR signaling in cancers and points out several possible convergence points. Wnt ligands can activate EGFR signaling through their 7-transmembrane domain receptor Frizzled while EGFR can activate β-catenin via receptor tyrosine kinase-PI3K/Akt pathway; EGFR has been shown to form a complex with β-catenin and increase the invasion and metastasis of cancer cells. NKD2, a Wnt antagonist by interacting with Dishevelled, also escorts TGFα-containing exocytic vesicles to the basolateral membrane of polarized epithelial cells. Down-regulation of NKD2 causes Wnt activation and TGFα misdelivery, suggesting its functions in cell homeostasis and prevention of tumorigenesis.