An Activated ErbB3/NRG1 Autocrine Loop Supports In Vivo Proliferation in Ovarian Cancer Cells

Sheng, Quan Z.; Liu, Xinggang; Fleming, Eleanor; Yuan, Karen; Piao, Huiying; Chen, Jinyun; Moustafa, Zeinab; Thomas, Roman K.; Greulich, Heidi; Schinzel, Anna C.; Zaghlul, Sara; Batt, David; Ettenberg, Seth A.; Meyerson, Matthew; Kung, Andrew L.; Hahn, William C.; Drapkin, Ronny; Livingston, David M.; Liu, Joyce F.

doi:10.1016/j.ccr.2010.03.014

Cited by 57 publications

(87 citation statements)

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“…Consistent with this, reduced HER3 expression by conditional knockout or LNA-based antisense molecule, designated as EZN-3920, in a polyoma-T model of breast cancer inhibits PI3K activation and tumor formation in this genetically engineered mouse model (21). In addition, siRNA and short hairpin RNA (shRNA)-directed downmodulation of HER3 resulted in tumor growth inhibition in lung adenocarcinoma (22) and decreased disease progression as well as prolonged survival in xenograft mouse models of ovarian cancer (13) or of HER2-overexpressing breast cancer (5). Furthermore, a recent study showed the sensitivity of a subset of head and neck cancers to HER2 kinase inhibitor is dependent on the co-expression of HER3 and its ligand neuregulin-1 (14).…”

Section: Introductionmentioning

confidence: 70%

“…To find suitable models for in vivo studies, we screened multiple cell lines that may depend on HER3 for growth (4,5,13,(31)(32)(33) and tested the effect of EZN-3920 on the growth of these lines. As transfection is highly artificial as recently reported (34) and does not represent the context of our in vivo experiments in which no transfection systems were used, the remainder of the in vitro studies were conducted without lipofection.…”

Section: Resultsmentioning

confidence: 99%

“…HER3 is overexpressed in various cancers, including breast, colon, gastric, prostate, lung, hepatocellular, head and neck cancers, and melanoma, and is implicated in tumorigenesis and prognosis (7)(8)(9)(10)(11). It is now clear that heregulin binding to HER3 or HER3 dimerization with EGFR or HER2 leads to hyperphosphorylation of cytoplasmic tail of HER3, which in turn results in AKT signaling (12)(13)(14). Beyond this, HER3 can be hyperphosphorylated in patients with gefitinib-resistant cancer (4) as well as lapatinib-or trastuzumab-resistant tumor cell lines via receptor tyrosine kinases (15,16).…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, a recent study showed the sensitivity of a subset of head and neck cancers to HER2 kinase inhibitor is dependent on the co-expression of HER3 and its ligand neuregulin-1 (14). In vitro, targeting HER3 using siRNAs and antisense deoxyoligonucleotides (AS-ODNs) potently inhibits proliferation and promotes apoptosis in cells sensitive and insensitive to EGFR and HER2 inhibitors (5,13,17,22,23). Finally, a monoclonal antibody to HER3 inhibited tumor growth, especially in cell lines that secrete heregulin, a ligand for HER3 (12).…”

Section: Introductionmentioning

confidence: 99%

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Downregulation of HER3 by a Novel Antisense Oligonucleotide, EZN-3920, Improves the Antitumor Activity of EGFR and HER2 Tyrosine Kinase Inhibitors in Animal Models

Zhang

Wang

et al. 2013

Molecular Cancer Therapeutics

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Among the four human EGF receptor (HER) family members (EGFR, HER2, HER3, HER4), HER3 is of particular interest as it interacts with HER2 and EGFR via heterodimerization and is a key link to the phosphoinositide 3-kinase (PI3K)/AKT signal transduction axis. Recent studies indicate that HER3 plays a critical role in mediating resistance to agents that target EGFR or HER2. As HER3 lacks significant kinase activity and cannot be inhibited by tyrosine kinase inhibitors, neutralizing antibodies and alternative inhibitors of HER3 have been sought as cancer therapeutics. We describe here a locked nucleic acid (LNA)-based HER3 antisense oligonucleotide, EZN-3920, that specifically downmodulated the expression of HER3, which was associated with growth inhibition. EZN-3920 effectively downmodulated HER3 expression, HER3-driven PI3K/AKT signaling pathway, and growth in tumors derived from BT474M1 breast and HCC827 lung carcinoma cell lines, which overexpress HER2 and EGFR, respectively. Furthermore, when EZN-3920 was coadministered with gefitinib or lapatinib in xenograft tumor models, enhanced antitumor activity compared with the effect of monotherapy was found. The effect was associated with a blockade of induced HER3 mRNA expression caused by lapatinib or gefitinib treatment. Finally, EZN-3920 sustained its antiproliferative effect in trastuzumab-resistant cells and three independently derived gefitinib-resistant cells. Our findings show that downmodulation of HER3 by EZN-3920 leads to the suppression of tumor growth in vitro and in vivo, suggesting that HER3 can be an effective target for the treatment of various cancers that have been activated by HER3 alone or where HER3 activation is associated with EGFR or HER2 expression.

show abstract

Section: Introductionmentioning

confidence: 70%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Downregulation of HER3 by a Novel Antisense Oligonucleotide, EZN-3920, Improves the Antitumor Activity of EGFR and HER2 Tyrosine Kinase Inhibitors in Animal Models

Zhang

Wang

et al. 2013

Molecular Cancer Therapeutics

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“…Moreover, the mechanism of action of cetuximab, an anti-EGFR Ab used to treat colorectal cancer, has been attributed to blockade of EGFR-specific ligands like amphiregulin (35). Likewise, ovarian tumors might depend on an autocrine loop involving HER3 and NRG1 (36).…”

Section: Discussionmentioning

confidence: 99%

Examination of HER3 targeting in cancer using monoclonal antibodies

Gaborit¹,

Abdul-Hai

Mancini³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The human EGF receptor (HER/EGFR) family of receptor tyrosine kinases serves as a key target for cancer therapy. Specifically, EGFR and HER2 have been repeatedly targeted because of their genetic aberrations in tumors. The therapeutic potential of targeting HER3 has long been underestimated, due to relatively low expression in tumors and impaired kinase activity. Nevertheless, in addition to serving as a dimerization partner of EGFR and HER2, HER3 acts as a key player in tumor cells’ ability to acquire resistance to cancer drugs. In this study, we generated several monoclonal antibodies to HER3. Comparisons of their ability to degrade HER3, decrease downstream signaling, and inhibit growth of cultured cells, as well as recruit immune effector cells, selected an antibody that later emerged as the most potent inhibitor of pancreatic cancer cells grown as tumors in animals. Our data predict that anti-HER3 antibodies able to intercept autocrine and stroma–tumor interactions might strongly inhibit tumor growth, in analogy to the mechanism of action of anti-EGFR antibodies routinely used now to treat colorectal cancer patients.

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Targeting HER2 in patient‐derived xenograft ovarian cancer models sensitizes tumors to chemotherapy

et al. 2018

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Ovarian cancer is the most lethal gynecologic malignancy. About 75% of ovarian cancer patients relapse and/or develop chemo‐resistant disease after initial response to standard‐of‐care treatment with platinum‐based therapies. HER2 amplifications and overexpression in ovarian cancer are reported to vary, and responses to HER2 inhibitors have been poor. Next generation sequencing technologies in conjunction with testing using patient‐derived xenografts (PDX) allow validation of personalized treatments. Using a whole‐genome mate‐pair next generation sequencing (MPseq) protocol, we identified several high grade serous ovarian cancers (HGS‐OC) with DNA alterations in genes encoding members of the ERBB2 pathway. The efficiency of anti‐HER2 therapy was tested in three different PDX lines with the identified alterations and high levels of HER2 protein expression. Treatment responses to pertuzumab or pertuzumab/trastuzumab were compared in each PDX line WITH standard carboplatin and paclitaxel combination treatment. In all three PDX models, HER2‐targeted therapy resulted in significant inhibition of tumor growth compared with untreated controls. However, the responses in each case were inferior to those to chemotherapy, even for chemo‐resistant lines. When chemotherapy and HER2‐targeted therapy were administered together, a significant regression of tumor was observed after 6 weeks of treatment compared with chemotherapy alone. Post‐treatment analysis of these tissues revealed that inhibition of the ERBB2 pathway occurred at the level of phosphorylation and expression of downstream targets. In conclusion, while targeting of presumably activated ERBB2 pathway alone in HGS‐OC results in a modest treatment benefit, a combination therapy including both chemotherapy drugs and HER2 inhibitors provides a far better response. Further studies are needed to address development of recurrence and sensitivity of recurrent disease to HER2‐targeted therapy.

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An Activated ErbB3/NRG1 Autocrine Loop Supports In Vivo Proliferation in Ovarian Cancer Cells

Cited by 57 publications

References 0 publications

Downregulation of HER3 by a Novel Antisense Oligonucleotide, EZN-3920, Improves the Antitumor Activity of EGFR and HER2 Tyrosine Kinase Inhibitors in Animal Models

Downregulation of HER3 by a Novel Antisense Oligonucleotide, EZN-3920, Improves the Antitumor Activity of EGFR and HER2 Tyrosine Kinase Inhibitors in Animal Models

Examination of HER3 targeting in cancer using monoclonal antibodies

Targeting HER2 in patient‐derived xenograft ovarian cancer models sensitizes tumors to chemotherapy

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