Dataset Information

Dual HER2 targeting impedes growth of HER2 gene-amplified uterine serous carcinoma xenografts.

ABSTRACT:

Purpose

Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer that commonly harbors HER2 gene amplification. We investigated the effectiveness of HER2 inhibition using lapatinib and trastuzumab in vitro and in xenografts derived from USC cell lines and USC patient-derived xenografts.

Experimental design

Immunohistochemistry and FISH were performed to assess HER2 expression in 42 primary USC specimens. ARK1, ARK2, and SPEC2 cell lines were treated with trastuzumab or lapatinib. Cohorts of mice harboring xenografts derived from ARK2 and SPEC2 cell lines and EnCa1 and EnCa2 primary human USC samples were treated with either vehicle, trastuzumab, lapatinib, or the combination of trastuzumab and lapatinib. Acute and chronic posttreatment tumor samples were assessed for downstream signaling alterations and examined for apoptosis and proliferation.

Results

HER2 gene amplification (24%) correlated significantly with HER2 protein overexpression (55%). All models were impervious to single-agent trastuzumab treatment. Lapatinib decreased in vitro proliferation of all cell lines and in vivo growth of HER2-amplified xenografts (ARK2, EnCa1). In addition, dual therapy with trastuzumab and lapatinib resulted in significant antitumor activity only in ARK2 and EnCa1 tumors. Dual HER2 therapy induced on target alteration of downstream MAPK and PI3K pathway mediators only in HER2-amplified models, and was associated with increased apoptosis and decreased proliferation.

Conclusions

Although trastuzumab alone did not impact USC growth, dual anti-HER2 therapy with lapatinib led to improved inhibition of tumor growth in HER2-amplified USC and may be a promising avenue for future investigation.

SUBMITTER: Groeneweg JW

PROVIDER: S-EPMC4268047 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Publications

Dual HER2 targeting impedes growth of HER2 gene-amplified uterine serous carcinoma xenografts.

Groeneweg Jolijn W JW Hernandez Silvia F SF Byron Virginia F VF DiGloria Celeste M CM Lopez Hector H Scialabba Vanessa V Kim Minji M Zhang Ling L Borger Darrell R DR Tambouret Rosemary R Foster Rosemary R Rueda Bo R BR Growdon Whitfield B WB

Clinical cancer research : an official journal of the American Association for Cancer Research 20141007 24

<h4>Purpose</h4>Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer that commonly harbors HER2 gene amplification. We investigated the effectiveness of HER2 inhibition using lapatinib and trastuzumab in vitro and in xenografts derived from USC cell lines and USC patient-derived xenografts.<h4>Experimental design</h4>Immunohistochemistry and FISH were performed to assess HER2 expression in 42 primary USC specimens. ARK1, ARK2, and SPEC2 cell lines were treated with trast ...[more]

PMID: 25294905

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Project description:Serous endometrial cancer represents a relative rare entity accounting for about 10% of all diagnosed endometrial cancer, but it is responsible for 40% of endometrial cancer-related deaths. Patients with serous endometrial cancer are often diagnosed at earlier disease stage, but remain at higher risk of recurrence and poorer prognosis when compared stage-for-stage with endometrioid subtype endometrial cancer. Serous endometrial cancers are characterized by marked nuclear atypia and abnormal p53 staining in immunohistochemistry. The mainstay of treatment for newly diagnosed serous endometrial cancer includes a multi-modal therapy with surgery, chemotherapy and/or radiotherapy. Unfortunately, despite these efforts, survival outcomes still remain poor. Recently, The Cancer Genome Atlas (TCGA) Research Network classified all endometrial cancer types into four categories, of which, serous endometrial cancer mostly is found within the "copy number high" group. This group is characterized by the increased cell cycle deregulation (e.g., CCNE1, MYC, PPP2R1A, PIKCA, ERBB2 and CDKN2A) and TP53 mutations (90%). To date, the combination of pembrolizumab and lenvatinib is an effective treatment modality in second-line therapy, with a response rate of 50% in advanced/recurrent serous endometrial cancer. Owing to the unfavorable outcomes of serous endometrial cancer, clinical trials are a priority. At present, ongoing studies are testing novel combinations of various targeted and immunotherapeutic agents in newly diagnosed and advanced/recurrent endometrial cancer - an important strategy for serous endometrial cancer, whereby tumors are usually p53+ and pMMR, making response to PD-1 inhibitor monotherapy unlikely. Here, the rare tumor working group (including members from the European Society of Gynecologic Oncology (ESGO), Gynecologic Cancer Intergroup (GCIG), and Japanese Gynecologic Oncology Group (JGOG)), performed a narrative review reporting on the current landscape of serous endometrial cancer and focusing on standard and emerging therapeutic options for patients affected by this difficult disease.

Project description:Background and objectiveSerous endometrial cancers (ECs) are an aggressive histotype of ECs which are disproportionately responsible for 40% of cancer-specific mortality rates despite constituting only 5-10% of all uterine cancers in incidence. In recent times, it has become increasingly evident that about 20-40% of uterine serous cancers (USCs) have molecular alterations in ERBB2 pathway with human epidermal growth factor receptor 2 (HER2/neu) amplification or overexpression. We summarise the evidence on genetic and molecular alterations in HER2/neu pathway in USC with a focus on testing criteria, targeting agents and resistance mechanisms.MethodsWe conducted a database search of PubMed/Medline up to 28th February 2023 for articles published in the English language using pre-defined search terms. One hundred and seventy-one relevant articles were subsequently reviewed for eligibility and inclusion in the review.Key content and findingsThe Cancer Genome Atlas (TCGA) classification is a significant development in the molecular profiling of ECs with a positive impact on the treatment of these tumors including USCs. Testing criteria for HER2/neu in USC with immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) has evolved in more than a decade with progress made towards EC specific testing guidelines. The findings of a recent phase III study have led to the development of practice changing guidelines towards improving patient outcomes.ConclusionsMolecular aberration in the HER2/neu pathway contributes to the aggressive behaviour of USC. Considering the clinical benefit conferred by HER2/neu targeted therapy, HER2/neu testing is recommended for all cases of serous EC in advanced and recurrent settings. Trastuzumab in combination with platinum and taxanes based chemotherapy is the recommended treatment option for patients with advanced or recurrent serous cancers who test positive to HER2/neu. Clinical trials on targeted therapy are ongoing and future research should focus on selection of patients who will derive the most benefit from such therapy.

Dataset Information

Dual HER2 targeting impedes growth of HER2 gene-amplified uterine serous carcinoma xenografts.

Purpose

Experimental design

Results

Conclusions

Publications

Dual HER2 targeting impedes growth of HER2 gene-amplified uterine serous carcinoma xenografts.

Similar Datasets

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