HER2 overexpression is identified on 20–30% breast cancer and other cancers at different levels. Although HER2 targeted monoclonal antibody combined with chemical drugs has shown improved outcomes in ...HER2 expressing patients, drug resistance and toxicity have limited their efficacy. To overcome drug resistance, cotargeting multiple HER receptors was proven to be effective. EGFR/HER2 dimerization can active PI3K/AKT pathway, and resistance to HER2-targeted drugs is associated with upregulation of EGFR. Here, we developed a novel HER2/EGFR targeted nucleic acid therapeutic to address current drug limits. The new therapeutic is constructed by fusing HER2 aptamer-EGFR siRNA sense strand with HER2 aptamer-EGFR siRNA antisense strand into one molecule: a bivalent HER2 aptamer-EGFR siRNA aptamer chimera (HEH). In breast cancer cell lines, HEH can be selectively taken up into HER2 expressing cells and successfully silence EGFR gene and down regulate HER2 expression. In breast cancer xenograft models, HEH is capable of triggering cell apoptosis, decreasing HER2 and EGFR expression, and suppressing tumor growth. The therapeutic efficacy of HEH is superior to HER2 aptamer only, which suggests that HEH has synergistic effect by targeting HER2 and EGFR. This study demonstrated that HEH has great potential as a new HER2 targeted drug to address toxicity and resistance of current drugs and may provide a cure for many HER2 positive cancers.
HER family members are interdependent and functionally compensatory. Simultaneously targeting EGFR/HER2/HER3 by antibody combinations has demonstrated superior treatment efficacy over targeting one ...HER receptor. However, antibody combinations have their limitations, with high immunogenicity and high cost. In this study, we have developed a three-in-one nucleic acid aptamer-small interfering RNA (siRNA) chimera, which targets EGFR/HER2/HER3 in one molecule. This inhibitory molecule was constructed such that a single EGFR siRNA is positioned between the HER2 and HER3 aptamers to create a HER2 aptamer-EGFR siRNA-HER3 aptamer chimera (H2EH3). EGFR siRNA was delivered into HER2-expressing cells by HER2/HER3 aptamer-induced internalization. HER2/HER3 aptamers act as antagonist molecules for blocking HER2 and HER3 signaling pathways and also as tumor-targeting agents for siRNA delivery. H2EH3 enables down-modulation of the expression of all three receptors, thereby triggering cell apoptosis. In breast cancer xenograft models, H2EH3 is able to bind to breast tumors with high specificity and significantly inhibits tumor growth via either systemic or intratumoral administration. Owing to low immunogenicity, ease of production, and high thermostability, H2EH3 is a promising therapeutic to supplement current single HER inhibitors and may act as a treatment for HER2+ breast cancer with intrinsic or acquired resistance to current drugs.
Trastuzumab is the first Food and Drug Administration (FDA)‐approved therapeutic targeting a HER‐family receptor tyrosine kinase (HER2/ErbB2/neu). Although trastuzumab is effective in the treatment ...of HER2‐positive breast cancer, a substantial proportion of patients will not respond to trastuzumab‐based regimens (primary resistance), and those who do respond will often lose clinical benefits (i.e., secondary resistance). Although multiple mechanisms underlying the development of secondary trastuzumab resistance have been identified, few studies have specifically examined the basis of primary trastuzumab resistance. Here, we review these studies, which together demonstrate that trastuzumab induces phenotypic changes in tumor cells, even when they are not growth inhibited by trastuzumab, including changes in gene expression. These changes have important clinical implications, including the sensitization of malignant cells to other therapeutic drugs. In light of these observations, we propose that the conventional definition of resistance as it pertains to trastuzumab and, perhaps, to other targeted therapeutics, may require revision. The results of these studies will be useful in informing the direction of future basic and clinical research focused on overcoming primary trastuzumab resistance.
Although trastuzumab (Herceptin) is an important advance in the treatment of breast cancer, a significant proportion of patients do not respond to trastuzumab either alone or in combination with ...chemotherapy. In this study, we observe that epidermal growth factor receptor (EGFR) and HER3 expression is substantially increased after long-term trastuzumab exposure of HER2-positive breast carcinoma-derived cell lines that show primary resistance to trastuzumab. Furthermore, long-term trastuzumab exposure of trastuzumab-resistant cell lines induces de novo sensitivity to the EGFR-targeted agents gefitinib or cetuximab in two of three cell lines accompanied by increased EGFR expression. Together, these results indicate that primary trastuzumab resistance is not synonymous with lack of responsiveness to trastuzumab and, importantly, suggest that trastuzumab priming may sensitize trastuzumab-resistant tumors to other HER family-directed therapeutics.
Background
Progressive maturation of growth plate chondrocytes drives long bone growth during endochondral ossification. Signals from the epidermal growth factor receptor (EGFR), and from bone ...morphogenetic protein‐2 (BMP2), are required for normal chondrocyte maturation. Here, we investigated cross‐talk between EGFR and BMP2 signals in developing and adult growth plates.
Results
Using in vivo mouse models of conditional cartilage‐targeted EGFR or BMP2 loss, we show that canonical BMP signal activation is increased in the hypertrophic chondrocytes of EGFR‐deficient growth plates; whereas EGFR signal activation is increased in the reserve, prehypertrophic and hypertrophic chondrocytes of BMP2‐deficient growth plates. EGFR‐deficient chondrocytes displayed increased BMP signal activation in vitro, accompanied by increased expression of IHH, COL10A1, and RUNX2. Hypertrophic differentiation and BMP signal activation were suppressed in normal chondrocyte cultures treated with the EGFR ligand betacellulin, effects that were partially blocked by simultaneous treatment with BMP2 or a chemical EGFR antagonist.
Conclusions
Cross‐talk between EGFR and BMP2 signals occurs during chondrocyte maturation. In the reserve and prehypertrophic zones, BMP2 signals unilaterally suppress EGFR activity; in the hypertrophic zone, EGFR and BMP2 signals repress each other. This cross‐talk may play a role in regulating chondrocyte maturation in developing and adult growth plates.
Key Findings
epidermal growth factor receptor, EGFR, bone morphogenetic protein, BMP2, BMP, chondrocyte maturation, hypertrophic chondrocyte, growth plate, betacellulin, BTC
Epidermal growth factor (EGF) and its receptor (EGFR) constitute a principal growth-promoting pathway in endometrial cancer cells. Pre-clinical studies were undertaken to compare the expression of ...EGFR isoforms and the downstream effects of activating or blocking EGFR function in Ishikawa H cells, derived from a moderately differentiated type I endometrioid adenocarcinoma, or in Hec50co cells, derived from a poorly differentiated type II adenocarcinoma with papillary serous sub-differentiation.
We investigated whether EGFR mutations are present in the tyrosine kinase domain (exons 18-22) of EGFR and also whether EGFR isoforms are expressed in the Ishikawa H or Hec50co cell lines. Sequence of the EGFR tyrosine kinase domain proved to be wild type in both cell lines. While both cell lines expressed full-length EGFR (isoform A), EGFR and sEGFR (isoform D) were expressed at significantly lower levels in Hec50co cells compared to Ishikawa H cells. Analysis of gene expression following EGF vs. gefitinib treatment (a small molecule EGFR tyrosine kinase inhibitor) was performed. Early growth response 1, sphingosine kinase 2, dual specificity phosphatase 6, and glucocorticoid receptor DNA binding factor 1 are members of a cluster of genes downstream of EGFR that are differentially regulated by treatment with EGF compared to gefitinib in Ishikawa H cells, but not in Hec50co cells.
Type I Ishikawa H and type II Hec50co endometrial carcinoma cells both express EGFR and sEGFR, but differ markedly in their responsiveness to the EGFR inhibitor gefitinib. This difference is paralleled by differences in the expression of sEGFR and EGFR, as well as in their transcriptional response following treatment with either EGF or gefitinib. The small cluster of differently regulated genes reported here in these type I vs. type II endometrial cancer-derived cell lines may identify candidate biomarkers useful for predicting sensitivity to EGFR blockade.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The ERBB or EGF receptor (EGFR) proto-oncogene family, which consists of four structurally-related transmembrane receptors (i.e., EGFR, ErbB2, ErbB3, and ErbB4), plays an etiological role in the ...molecular pathogenesis of cancer and is a key therapeutic target in many types of cancer, including ovarian cancer. These ErbB/EGF receptor tyrosine kinases play important physiologic roles in cell proliferation, survival, adhesion, motility, invasion, and angiogenesis. It is, therefore, not surprising that gene amplification, genetic mutation, and altered transcription/translation result in aberrant ErbB/EGF receptor expression and/or signal transduction, contributing to the development of malignant transformation. Clinically, the diagnostic, prognostic, and theragnostic significance of any single ErbB receptor and/or ErbB ligand is controversial, but generally, ErbB receptor overexpression has been correlated with poor prognosis and decreased therapeutic responsiveness in ovarian cancer patients. Thus, anticancer agents targeting ErbB/EGF receptors hold great promise for personalized cancer treatment. Yet, challenges remain in designing prospective clinical trials to assess the clinical utility of ErbB receptors and their ligands to diagnose cancer; to predict progression-free and overall survival, therapeutic responsiveness, and disease recurrence; and to monitor treatment responsiveness. Here, we review the tissue expression and serum biomarker studies that have evaluated the diagnostic, prognostic, and theragnostic utility of ErbB/EGF receptors, their circulating soluble isoforms (sEGFR/sErbBs), and their cognate ligands in ovarian cancer patients.
The RNA binding protein Lin28 and its paralog Lin28B are associated with advanced human malignancies. Blocking the biogenesis of let-7 miRNA, a tumor suppressor, by Lin28/Lin28B has been thought to ...underlie their roles in cancer. Here we report that the mRNA for the human epidermal growth factor receptor 2 (HER2), a HER-family receptor tyrosine kinase known to play a critical role in cell proliferation and survival and also a major therapeutic target in breast cancer, is among several targets of Lin28 regulation. We show that Lin28 stimulates HER2 expression at the posttranscriptional level, and that enforced Lin28 expression promotes cancer cell growth via multiple mechanisms. Consistent with its pleiotropic role in regulating gene expression, Lin28 overexpression in primary breast tumors is a powerful predictor of poor prognosis, representing the first report on the impact of Lin28 expression on clinical outcome in human cancer. While revealing another layer of regulation of HER2 expression in addition to gene amplification, our studies also suggest novel mechanistic insights linking Lin28 expression to disease outcome and imply that targeting multiple pathways is a common mechanistic theme of Lin28-mediated regulation in cancer.
Signals from the epidermal growth factor receptor (EGFR) have typically been considered to provide catabolic activities in articular cartilage, and accordingly have been suggested to have a causal ...role in osteoarthritis progression. The aim of this study was to determine in vivo roles for endogenous EGFR signal activation in articular cartilage.
Transgenic mice with conditional, limb-targeted deletion of the endogenous intracellular EGFR inhibitor Mig-6 were generated using CreLoxP (Mig-6-flox; Prx1Cre) recombination. Histology, histochemical staining and immunohistochemistry were used to confirm activation of EGFR signaling in the articular cartilage and joints, and to analyze phenotypic consequences of Mig-6 loss on articular cartilage morphology, proliferation, expression of progenitor cell markers, presence of chondrocyte hypertrophy and degradation of articular cartilage matrix.
The articular cartilage of Mig-6-conditional knockout (Mig-6-cko) mice was dramatically and significantly thicker than normal articular cartilage at 6 and 12 weeks of age. Mig-6-cko articular cartilage contained a population of chondrocytes in which EGFR signaling was activated, and which were three to four times more proliferative than normal Mig-6-flox articular chondrocytes. These cells expressed high levels of the master chondrogenic regulatory factor Sox9, as well as high levels of putative progenitor cell markers including superficial zone protein (SZP), growth and differentiation factor-5 (GDF-5) and Notch1. Expression levels were also high for activated β-catenin and the transforming growth factor beta (TGF-β) mediators phospho-Smad2/3 (pSmad2/3). Anabolic effects of EGFR activation in articular cartilage were followed by catabolic events, including matrix degradation, as determined by accumulation of aggrecan cleavage fragments, and onset of hypertrophy as determined by type × collagen expression. By 16 weeks of age, the articular cartilage of Mig-6-cko knees was no longer thickened and was degenerating.
These results demonstrate unexpected anabolic effects of EGFR signal activation in articular cartilage, and suggest the hypothesis that these effects may promote the expansion and/or activity of an endogenous EGFR-responsive cell population within the articular cartilage.
In September 2018, the 12th Biennial Ovarian Cancer Research Symposium was presented by the Rivkin Center for Ovarian Cancer and the American Association for Cancer Research, in Seattle, WA, USA. The ...2018 Symposium focused on four broad areas of research: Detection and Prevention of Ovarian Cancer, Genomics and Molecular Mechanisms of Ovarian Cancer, Tumor Microenvironment and Immunology of Ovarian Cancer, and Novel Therapeutics: Response and Resistance of Ovarian Cancer. In addition, a special panel on the 'Role of Advocates in Ovarian Cancer Research' was featured.
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