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Dacomitinib, a pan-inhibitor of ErbB receptors, suppresses growth and invasive capacity of chemoresistant ovarian carcinoma cells.

ABSTRACT: Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy worldwide. Development of chemoresistance and peritoneal dissemination of EOC cells are the major reasons for low survival rate. Targeting signal transduction pathways which promote therapy resistance and metastatic dissemination is the key to successful treatment. Members of the ErbB family of receptors are over-expressed in EOC and play key roles in chemoresistance and invasiveness. Despite this, single-targeted ErbB inhibitors have demonstrated limited activity in chemoresistant EOC. In this report, we show that dacomitinib, a pan-ErbB receptor inhibitor, diminished growth, clonogenic potential, anoikis resistance and induced apoptotic cell death in therapy-resistant EOC cells. Dacominitib inhibited PLK1-FOXM1 signalling pathway and its down-stream targets Aurora kinase B and survivin. Moreover, dacomitinib attenuated migration and invasion of the EOC cells and reduced expression of epithelial-to-mesenchymal transition (EMT) markers ZEB1, ZEB2 and CDH2 (which encodes N-cadherin). Conversely, the anti-tumour activity of single-targeted ErbB agents including cetuximab (a ligand-blocking anti-EGFR mAb), transtuzumab (anti-HER2 mAb), H3.105.5 (anti-HER3 mAb) and erlotinib (EGFR small-molecule tyrosine kinase inhibitor) were marginal. Our results provide a rationale for further investigation on the therapeutic potential of dacomitinib in treatment of the chemoresistant EOC.

SUBMITTER: Momeny M

PROVIDER: S-EPMC5482808 | biostudies-other | 2017 Jun

REPOSITORIES: biostudies-other

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Dacomitinib, a pan-inhibitor of ErbB receptors, suppresses growth and invasive capacity of chemoresistant ovarian carcinoma cells.

Momeny Majid M Zarrinrad Ghazaleh G Moghaddaskho Farima F Poursheikhani Arash A Sankanian Ghazaleh G Zaghal Azam A Mirshahvaladi Shahab S Esmaeili Fatemeh F Eyvani Haniyeh H Barghi Farinaz F Sabourinejad Zahra Z Alishahi Zivar Z Yousefi Hassan H Ghasemi Reza R Dardaei Leila L Bashash Davood D Chahardouli Bahram B Dehpour Ahmad R AR Tavakkoly-Bazzaz Javad J Alimoghaddam Kamran K Ghavamzadeh Ardeshir A Ghaffari Seyed H SH

Scientific reports 20170623 1

Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy worldwide. Development of chemoresistance and peritoneal dissemination of EOC cells are the major reasons for low survival rate. Targeting signal transduction pathways which promote therapy resistance and metastatic dissemination is the key to successful treatment. Members of the ErbB family of receptors are over-expressed in EOC and play key roles in chemoresistance and invasiveness. Despite this, single-targeted ErbB ...[more]

PMID: 28646172

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Project description:Glioblastoma in adults, and medulloblastoma and pineoblastoma that mainly affect children, are aggressive brain tumors. The survival for patients with glioblastoma remains dismal. While the cure rate for medulloblastoma exceeds 70%, this figure has stagnated over the past few decades and survivors still contend with significant long-term debilitating side effects. The prognosis for pineoblastoma is age-dependent, with little chance of a cure for children younger than three years. More effective molecularly targeted strategies are urgently required to treat these cancers. Hyper-activation of epidermal growth factor receptor (EGFR) signaling is characteristic of several different classes of human cancers, including a subset of glioblastoma and medulloblastoma. This has provided the impetus for the development of a suite of EGFR pathway blockers, including second generation irreversible inhibitors, such as dacomitinib. We have developed a comprehensive drug evaluation pipeline, including in vitro interaction analyses and orthotopic xenograft mouse models, to address the efficacy of drugs for brain tumor treatment, enabling the exclusion of potentially ineffective treatments and prioritization of truly beneficial novel treatments for clinical trial. We used this system to examine the effects of dacomitinib as a single agent, or in combination with conventional chemotherapeutics, on the growth of human adult and pediatric brain tumor cell lines. Dacomitinib inhibited EGFR or EGFRvIII activity in vitro in all three tumor types tested, and as a single agent induced a modest increase in survival time for mice bearing glioblastoma, which accurately predicted human clinical trial data. For pediatric medulloblastoma, dacomitinib blocked EGFR/HER signalling in orthotopic xenografts and extended median survival as a single agent, however was antagonistic when used in combination with standard frontline medulloblastoma chemotherapies. The findings caution against the use of dacomitinib for pediatric brain tumor clinical trials.

Dataset Information

Dacomitinib, a pan-inhibitor of ErbB receptors, suppresses growth and invasive capacity of chemoresistant ovarian carcinoma cells.

Publications

Dacomitinib, a pan-inhibitor of ErbB receptors, suppresses growth and invasive capacity of chemoresistant ovarian carcinoma cells.

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