Fulvestrant regulates epidermal growth factor (EGF) family ligands to activate EGF receptor (EGFR) signaling in breast cancer cells

Xi-hong, Zhang; Diaz, Michael R.; Yee, Douglas

doi:10.1007/s10549-013-2541-y

Cited by 19 publications

(15 citation statements)

References 36 publications

(40 reference statements)

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“…Additionally, in lung cancer cell lines, a recent study showed benefit of combining anti-EGFR and anti-estrogen (47). Although multiple studies have shown interaction between EGFR and ERα pathways (48, 49), further study is needed to elucidate the role of RET, EGFR, and VEGFRs in determining growth characteristics, interaction with hormone signaling pathways, and mediating the anti-tumor effects of vandetanib in luminal breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of RET Increases the Efficacy of Antiestrogen and Is a Novel Treatment Strategy for Luminal Breast Cancer

Spanheimer

Park

Askeland

et al. 2014

Clinical Cancer Research

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Purpose Recent findings suggest that combination treatment with anti-estrogen and anti-RET may offer a novel treatment strategy in a subset of breast cancer patients. We investigated the role of RET in potentiating the effects of anti-estrogen response and examined whether RET expression predicted the ability for tyrosine kinase inhibitor (TKI) to affect ERK1/2 activation in primary breast cancer. Experimental Design Growth response, ERK1/2 activation, Ki-67 and TUNEL were assessed in breast cancer cell lines in vitro and in xenografts with vandetanib and/or tamoxifen. Thirty tumors with matched normal breast tissue were evaluated for RET expression and response to TKI treatment. Results Vandetanib potentiated the inhibitory effect of tamoxifen in hormone responsive (p=0.01) and hormone insensitive (p<0.001) ERα-positive breast cancer cells. Vandetanib significantly repressed tumorigenesis of MCF-7 xenografts (p<0.001), which displayed decreased activation of ERK1/2 and AKT. Vandetanib and tamoxifen reduced the growth of established tumors with a greater effect of dual therapy compared to single agent (p=0.003), with tamoxifen reducing proliferative index and vandetanib inducing apoptosis. In primary breast cancers, RET expression correlated with the ERα-positive subtype. Relative decrease in ERK1/2 phosphorylation with TKI treatment was 42% (p<0.001) in RET-positive tumors vs. 14% (p=ns) in RET-negative tumors. Conclusions Vandetanib potentiated the anti-growth effects of tamoxifen in breast cancer, which was mediated through RET activation. RET predicted response to TKI therapy with minimal effects on ERK1/2 activation in RET-negative tumors. The preclinical data support evaluation of anti-estrogen in combination with TKI as a potential treatment strategy for RET-positive luminal breast cancer.

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Section: Discussionmentioning

confidence: 99%

Inhibition of RET Increases the Efficacy of Antiestrogen and Is a Novel Treatment Strategy for Luminal Breast Cancer

Spanheimer

Park

Askeland

et al. 2014

Clinical Cancer Research

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“…Fulvestrant was shown to differentially regulate EGFR ligands in breast cancer cells. 28 In fact, a major mechanism of acquired resistance to endocrine therapy in breast cancer is HER2/HER3 overactivation. 29 HER2/HER3 signaling is potently induced by NRG1-b1, which is highly induced by fulvestrant in NSCLC cells, an effect that was abrogated by adding dacomitinib.…”

Section: Discussionmentioning

confidence: 99%

Inhibiting Pathways Predicted From a Steroid Hormone Gene Signature Yields Synergistic Antitumor Effects in NSCLC

Almotlak

Farooqui

Siegfried

2020

Journal of Thoracic Oncology

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Introduction: Mounting evidence supports a role for estrogen signaling in NSCLC progression. We previously reported a seven-gene signature that predicts prognosis in estrogen receptor b positive (ERbþ) NSCLC. The signature defines a network comprised of ER and human EGFR-2/3 (HER2/HER3) signaling. Methods: We tested the efficacy of combining the pan-HER inhibitor, dacomitinib, with the estrogen antagonist, fulvestrant, in ERbþ NSCLC models with differing genotypes. We assessed the potency of this combination on xenograft growth and survival of host mice, and the ability to reverse the gene signature associated with poor outcome. Results: Synergy was observed between dacomitinib and fulvestrant in three human ERbþ NSCLC models: 201T (wild-type EGFR), A549 (KRAS mutant), and HCC827 (EGFR 19 deletion) with combination indices of 0.1-0.6. The combination, but not single agents, completely reversed the gene signature associated with poor prognosis in a mechanism that is largely mediated by activator protein 1 downregulation. In vivo, the combination also induced tumor regression and reversed the gene signature. In HCC827 xenografts treated with the combination, survival of mice was prolonged after therapy discontinuation, tumors that recurred were less aggressive, and two mechanisms of HER inhibitor resistance involving c-Met activation and PTEN loss were blocked. Conclusions: The combination of an ER blocker and a pan-HER inhibitor provides synergistic efficacy in different models of ERbþ NSCLC. Our data support the use of this combination clinically, considering its ability to induce potent antitumor effects and produce a gene signature that predicts better clinical outcomes.

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“…17,18 The binding of fulvestrant with ER also leads to a rapid degradation of the fulvestrant-ER complex and makes the receptor unavailable to estrogens, so the ability of ER to promote gene transcription is attenuated. 19 Endocrine therapy is known to be successful in treating most patients with advanced HR +/HER2− breast cancer; however, in many cases there is a relapse and the disease becomes refractory to such approaches. 20 There are many reasons for this resistance, but the factors involved include activation of mutations in the ESR1 gene encoding for ER; an increase in CDK4/6 activity; and upregulation of signaling pathways, such as phosphoinositide-3-kinase (PI3K)/AKT/mTOR and activated protein HER2/mitogenic kinase (MAPK).…”

Section: The Backbone: Fulvestrantmentioning

confidence: 99%

<p>Fulvestrant in Combination with CDK4/6 Inhibitors for HER2- Metastatic Breast Cancers: Current Perspectives</p>

Iorfida¹,

Mazza²,

Munzone³

2020

BCTT

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The development of CDK 4/6 inhibitors has dramatically changed the therapeutic management of hormone receptor-positive (HR+) and HER2 negative metastatic breast cancer (MBC). In combination with fulvestrant, palbociclib, ribociclib and abemaciclib have each been approved for HR+/HER2-MBC following the results of randomized Phase III studies (PALOMA-3, MONALEESA-3, MONARCH-2) and shown a significant advantage in PFS. Data from clinical trials support the combination with aromatase inhibitors in the first line setting and with fulvestrant in the second line. Each agent is well tolerated, and most of the toxicities observed with this class of drugs are generally easily manageable and free from particular complications. The latest evidence from MONARCH-2 and MONALEESA-3 trials shows benefits in terms of overall survival (OS), suggesting an option of using fulvestrant in combination with CDK 4/6 inhibitors in the first line setting. Additional research is needed to determine optimal treatment sequencing, understand the mechanisms of resistance, and develop novel therapeutic strategies to overcome clinical resistance and further improve the outcomes of patients with HR+/HER-MBC. Key questions in the field include the further impact on progression-free survival, overall survival, and the role of continuing CDK 4/6 blockade beyond progression. The purpose of this review is to describe the clinical relevance of fulvestrant in combination with CDK 4/6 inhibitors in HR+/HER2-MBC patients, as well as to discuss the current controversies and evolving research areas.

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Fulvestrant regulates epidermal growth factor (EGF) family ligands to activate EGF receptor (EGFR) signaling in breast cancer cells

Cited by 19 publications

References 36 publications

Inhibition of RET Increases the Efficacy of Antiestrogen and Is a Novel Treatment Strategy for Luminal Breast Cancer

Inhibition of RET Increases the Efficacy of Antiestrogen and Is a Novel Treatment Strategy for Luminal Breast Cancer

Inhibiting Pathways Predicted From a Steroid Hormone Gene Signature Yields Synergistic Antitumor Effects in NSCLC

<p>Fulvestrant in Combination with CDK4/6 Inhibitors for HER2- Metastatic Breast Cancers: Current Perspectives</p>

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