No abstract

Receptor tyrosine kinases (RTKs) are in the focus of targeted therapy for epithelial tumors. Our study addressed the role of EGFR, HER2 and HER3 expression and dimerization in esophageal cancers in situ and in vitro in the context of therapeutic EGFR and HER2 inhibitors. In archival pretreatment biopsies of esophageal carcinomas (n 5 110), EGFR was preferentially expressed in esophageal squamous cell carcinomas (ESCCs) (22.4%; p 5 0.088) and HER2 (34.4%; p < 0.001) with HER3 (91.5%; p < 0.001) in esophageal (Barrett's) adenocarcinomas (EACs). In situ proximity ligation assays revealed mainly EGFR and HER2 homodimers in ESCC and EAC cases, respectively. However, EAC cases also exhibited HER2/HER3 heterodimers. In vitro ESCC (OE21) cells displayed a significant response to erlotinib, gefitinib and lapatinib, with loss of AKT phosphorylation, G0/G1 cell cycle arrest and induction of apoptosis. In EAC cells (OE19, OE33 and SK-GT-4), lapatinib was similarly effective in strongly HER2-positive (mainly HER2 homodimers and some HER2/EGFR heterodimers) OE19 and OE33 cells. The HER2-targeting antibodies (trastuzumab and pertuzumab) given alone were largely ineffective in ESCC and EAC cells. However, both antibodies significantly induced antibody-dependent cellular cytotoxicity in EAC (OE19 and OE33) cells upon co-culture with peripheral blood mononuclear cells. The study reveals that overexpression of EGFR and HER2 predominantly results in homodimers in ESCCs and EACs, respectively. Still, some EACs also show HER2 dimerization plasticity, e.g., with HER3. Such RTK dimerization patterns affect responses to EGFR and HER2 targeting inhibitors in ESCC and EAC cells in vitro and hence may influence future prediction for particularly HER2-targeting inhibitors in EACs.Receptor tyrosine kinases (RTKs) of the EGFR family are involved in development and progression of several epithelial tumors and hence represent therapeutic targets for inhibition by small-molecule tyrosine kinase inhibitors (TKIs) or humanized monoclonal antibodies (mABs) in advanced lung, colorectal, breast and gastric cancer patients.1,2 Thus far, RTK gene amplification or protein expression and alterations of RTK-associated downstream signaling molecules are considered as important factors predicting the response to RTK inhibitors in such epithelial cancer patients. 3In the two main histotypes of esophageal cancer 3-6 -esophageal (Barrett's) adenocarcinomas (EACs) and esophageal squamous cell carcinomas (ESCCs)-gene amplification and/or protein (over)expression of the RTKs EGFR and

The malignant growth of human papillomavirus (HPV)‐positive cancer cells is dependent on the continuous expression of the viral E6/E7 oncogenes. Here, we examined the effects of iron deprivation on the phenotype of HPV‐positive cervical cancer cells. We found that iron chelators, such as the topical antifungal agent ciclopirox (CPX), strongly repress HPV E6/E7 oncogene expression, both at the transcript and protein level. CPX efficiently blocks the proliferation of HPV‐positive cancer cells by inducing cellular senescence. Although active mTOR signaling is considered to be critical for the cellular senescence response towards a variety of prosenescent agents, CPX‐induced senescence occurs under conditions of severely impaired mTOR signaling. Prolonged CPX treatment leads to p53‐independent Caspase‐3/7 activation and induction of apoptosis. CPX also eliminates HPV‐positive cancer cells under hypoxic conditions through induction of apoptosis. Taken together, these results show that iron deprivation exerts profound antiviral and antiproliferative effects in HPV‐positive cancer cells and suggest that iron chelators, such as CPX, possess therapeutic potential as HPV‐inhibitory, prosenescent and proapoptotic agents in both normoxic and hypoxic environments.