Effect of the molecular targeted drug, erlotinib, against endometrial cancer expressing high levels of epidermal growth factor receptor

Abstract

BackgroundThe epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, erlotinib, has been clinically applied for the treatment of a variety of tumors with EGFR overexpression. A phase II clinical study of erlotinib (NCIC IND-148) for recurrent or metastatic endometrial carcinoma (EC) resulted in an unfavorable result. However, in that study, the expression levels of EGFR were not accurately analyzed. Thus, the aim of this study was to re-examine the efficacy of erlotinib in EC cells by utilizing in vitro and in vivo models.MethodsTissue samples obtained from patients histologically diagnosed with EC of the uterine corpus were subjected to immunohistochemistry and RT-PCR to determine the protein and mRNA expression levels of EGFR. Western blot and WST-1 assays of EGFR siRNA-transfected HEC-1A, KLE, and Ishikawa cells were used to evaluate the efficacy of erlotinib in tumor cell lines expressing different EGFR levels. Furthermore, HEC-1A and Ishikawa cells were implanted into athymic mice treated with either erlotinib or trastuzumab.ResultsAt our institution, 20.9 % of endometrial cancer patients with low grade endometrioid histology have been diagnosed as stage III and IV. Immunohistochemical analysis and RT-PCR revealed the presence of significant EGFR and EGFR mRNA expression in low-grade endometrioid carcinoma in comparison with high-grade endometrioid carcinoma. In vitro study, WST-1 assay and Western blot analysis revealed that EGFR expression levels were correlated with tumor cell viability. Erlotinib reduced the proliferation of HEC-1A expressing high levels of EGFR, while trastuzumab showed similar effect in Ishikawa cells dominantly expressing human epidermal growth factor receptor type2 (HER2). In vivo erlotinib decreased tumor growth in mice xenografted with HEC-1A cells, whereas this tumor-growth inhibition was not observed in trastuzumab-treated mice xenografted with Ishikawa cell.ConclusionsEGF contributed to tumor proliferation in EC cell lines along with EGFR expression in vitro. Erlotinib also demonstrated anti-tumor effects in xenograft mice models. Our results suggest that erlotinib continues to have clinical usefulness in specific cases, after taking into consideration the EGFR expression levels.

Treatment with aromatase inhibitors stimulates the expression of epidermal growth factor receptor-1 and neuregulin 1 in ER positive/HER-2/neu non-amplified primary breast cancers

“…The biological effects related to changes in EGFR/HER-1 and NRG1 expression that we report in the present study should be examined in more detail. In vitro it has been shown that a small increase in EGFR/HER-1 mRNA expression leads to marked changes in EGFR/HER-1 protein levels [81]. Small changes in gene expression may have important phenotypic effects depending on the type of gene.…”

Malignant mixed ovarian germ cell tumor composed of immature teratoma, yolk sac tumor and embryonal carcinoma harboring an EGFR mutation: a case report

“…To date, anti-EGFR antibody, anti-EGFR, or dual EGFR/HER2 tyrosine kinase inhibitors have been evaluated across a variety of disease types. 16 , 42 Clinical trials of EGFR-targeted therapeutics for the treatment of ovarian cancer over the past decade have yielded only modest results to date. 40 Recent evidence suggests that some somatic ERBB receptor mutations render resistance to FDA-approved EGFR inhibitors.…”

“… 15 Recently, EGFR has been shown to be overexpressed in many human cancers, including lung, central nervous system, head and neck, bladder, pancreas, breast, and uterine corpus; and it correlates with poor prognosis. 16 Therapies targeting EGFR signaling pathway are part of the arsenal of agents that are used to treat lung, colorectal, pancreatic, and head and neck cancers. 17 To the best of our knowledge, there have been no reports of EGFR mutation in MOGCT so far.…”

N-Butyl-2-cyanoacrylate-based injectable and in situ-forming implants for efficient intratumoral chemotherapy

“…For example, cetuximab and panitumumab target epidermal growth factor receptor (EGFR) to treat colorectal cancer (Braig et al, 2015), trastuzumab targets HER2 to treat breast cancer (Mayor, 2006), and rituximab targets CD20 to treat leucocythemia (Arzoo et al, 2002). Small-molecule targeted anti-tumor drugs have also been greatly advanced (Nishimura et al, 2015). Imitinib is a tyrosine-kinase inhibitor used in the treatment of multiple cancers, most notably Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML).…”