Non-HER2 signaling pathways activated in resistance to anti-HER2 therapy in breast cancer

Madrid-Paredes, Adela; Cañadas-Garre, Marisa; Sánchez–Pozo, Antonio; Calleja‐Hernández, Miguel Ángel

doi:10.1007/s10549-015-3578-x

Cited by 20 publications

(20 citation statements)

References 101 publications

(159 reference statements)

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“…A therapeutic strategy for cancers that are refractory to anti-ERBB2 and/or anti-EGFR therapy is therefore to use mTOR or Src inhibitors, in combination with anti-HER inhibitors 1 . Use of saracatinib in combination with lapatinib has been shown to synergistically inhibit proliferation, migration, and invasion in lapatinib resistant cell lines 6 . In preclinical models of trastuzumab resistance, use of mTOR inhibitors has resulted in enhanced anti-proliferative effects, and there is some clinical evidence for the utility of mTOR inhibition in hormone receptor-positive and HER2-positive breast cancers 15,22,23 .…”

Section: Discussionmentioning

confidence: 99%

“…In an effort to achieve greater response rates, trastuzumab and lapatanib/gefitnib combination therapies have been attempted 5 . Unfortunately, responses to such combination therapies have also been fraught with resistance arising from compensatory signaling molecules or pathways 1,6 . There is, therefore, a need for studying other effectors or modulators that influence the durability of response and/or by-pass resistance to HER2-targeted therapies.…”

Section: Introductionmentioning

confidence: 99%

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ESE-1 Knockdown Attenuates Growth in Trastuzumab-resistant HER2+ Breast Cancer Cells

Kar

Gutierrez‐Hartmann

2017

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Abstract. Background Trastuzumab, also known as Herceptin, is a monoclonal antibody that interrupts HER2-mediated downstream signaling by various mechanisms (1-3). In combination with chemotherapy, trastuzumab has been shown to increase overall survival in HER2 + breast cancer patients (4). However, only 30% of all HER2 + breast cancer patients respond to trastuzumab, and often duration of response to trastuzumab lasts only 5 to 9 months, indicating that both primary and acquired resistance to trastuzumab is common. Combination therapies with lapatinib and gefitinib have also been fraught with resistance arising from compensatory signaling molecules or pathways (1, 5). There is, therefore, a need for studying other effectors or modulators that influence the durability of response and/or by-pass resistance to HER2-targeted therapies.Several ETS transcription factors, such as ETS-1, ESE-1/Elf-3, ESE-2/Elf5 and PEA-3, appear to be important in human breast cancer. ESE-1 is particularly relevant in HER2 + breast cancer, because ESE-1 regulates the HER2 + promoter activity and protein levels (6). In parental BT474 and SKBR3 cells, ESE-1 controls HER2 dependent signaling and tumorigenesis (7). Moreover, neuregulin and other growth factor ligands induce ESE-1 expression (8), revealing an additional feedforward level of control of ESE-1 and downstream effectors targeted by trastuzumab.In this paper, we investigated the role of ESE-1 in controlling transformation in trastuzumab-resistant HER2 -positive cell lines derived from parental HER2 + , ER + BT474 and HER2 + , ER -SKBR3 breast cancer cell lines. These trastuzumab-resistant cell lines develop an interaction between HER2, HER3/ErbB3 and IGF-1R to form a hetero-trimeric receptor signaling complex as the mechanism mediating trastuzumab resistance (9). Investigating ESE-1's role in the context of trastuzumab-resistance showed that knockdown of ESE-1 inhibits proliferation, clonogenicity and anchorageindependent growth in both resistant cell lines specifically by modulating several signaling molecules. Furthermore, lack of any synergistic inhibitory response of trastuzumab plus ESE-1 knockdown in the parental lines revealed that HER2 and ESE-1 function in the same pathway. Taken together, these studies highlight ESE-1 as a by-pass effector in HER2 resistance and establish the utility of pursuing ESE-1 as a future therapeutic target to inhibit the counter-regulatory responses to trastuzumab-mediated tumor inhibition. Materials and MethodsCell lines and cell culture. Cell lines BT474 and SKBR3 were purchased from the tissue culture core at University of Colorado Anschutz Medical Campus and the trastuzumab resistant cell lines HR20 and Pool2 were provided by Dr. Bolin Liu. All cell lines were 6583 This Αrticle is freely accessible online.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ESE-1 Knockdown Attenuates Growth in Trastuzumab-resistant HER2+ Breast Cancer Cells

Kar

Gutierrez‐Hartmann

2017

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“…Human epidermal growth factor receptor 2 (HER2) is amplified in up to 20% of primary breast cancers and is associated with aggressive tumor features . The anti‐HER2 monoclonal antibodies trastuzumab and pertuzumab, as well as the kinase inhibitor lapatinib, which targets epidermal growth factor receptor (EGFR) and HER2, have been approved for HER2‐positive breast cancer and have been shown to provide clinical benefits, but primary and acquired resistance to these drugs is common …”

Section: Introductionmentioning

confidence: 99%

STAT3 activation confers trastuzumab‐emtansine (T‐DM1) resistance in HER2‐positive breast cancer

Wang

Gao

et al. 2018

Cancer Science

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Trastuzumab‐emtansine (T‐DM1) is an antibody‐drug conjugate that has been approved for the treatment of human epidermal growth factor receptor 2 (HER2)‐positive metastatic breast cancer. Despite the remarkable efficacy of T‐DM1 in many patients, resistance to this therapeutic has emerged as a significant clinical problem. In the current study, we used BT‐474/KR cells, a T‐DM1‐resistant cell line established from HER2‐positive BT‐474 breast cancer cells, as a model to investigate mechanisms of T‐DM1 resistance and explore effective therapeutic regimens. We show here for the first time that activation of signal transducer and activator of transcription 3 (STAT3) mediated by leukemia inhibitory factor receptor (LIFR) overexpression confers resistance to T‐DM1. Moreover, secreted factors induced by activated STAT3 in resistant cells limit the responsiveness of cells that were originally sensitive to T‐DM1. Importantly, STAT3 inhibition sensitizes resistant cells to T‐DM1, both in vitro and in vivo, suggesting that the combination T‐DM1 with STAT3‐targeted therapy is a potential treatment for T‐DM1‐refractory patients.

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“…ER-negative BCs (luminal B, HER2-type, and basal-type) are often associated with aggressive disease, including amplification of HER2 or c- Myc oncogenes and mutation of the p53 gene [2, 11]. The use of monoclonal antibody to HER2 (trastuzumab, Herceptin®) has been deployed to treat HER2(+) BC, but the prognosis of such patients is poor since >60% of them experience relapse during the first year due to HER2 modifications, defects in the antibody dependent cellular cytotoxicity, or alterations in HER2 signaling pathways [12, 13]. …”

Section: Introductionmentioning

confidence: 99%

Clinical applications of mouse models for breast cancer engaging HER2/neu

Fry

Taneja

Inoue

2016

Integr Cancer Sci Therap.

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Human c-ErbB2 (HER2) has long been used as a marker of breast cancer (BC) for sub-categorization for the prediction of prognosis, and determination of therapeutic strategies. HER2 overexpressing BCs are more invasive/metastatic; but patients respond to monoclonal antibody therapy with trastuzumab or tyrosine kinase inhibitors, at least at early stages. To date, numerous mouse models that faithfully reproduce HER2(+) BCs have been created in mice. We recently reviewed different mouse models of BC overexpressing wild type or mutant neu driven by MMTV, neu, or doxycycline-inducible promoters. These mice have been used to demonstrate the histopathology, oncogenic signaling pathways initiated by aberrant overexpression of HER2 in the mammary epithelium, and interaction between oncogenes and tumor suppressor genes at molecular levels. In this review, we focus on their clinical applications. They can be used to test the efficacy of HER(2) inhibitors before starting clinical trials, characterize the tumor-initiating cells that could be the cause of relapse after therapy as well as to analyze the molecular mechanisms of therapeutic resistance targeting HER2. MMTV-human ErbB2 (HER2) mouse models have recently been established since the monoclonal antibody to HER2 (trastuzumab; Herceptin®) does not recognize the rat neu protein. It has been reported that early intervention with HER2 monoclonal antibody would be beneficial for preventing mammary carcinogenesis. MDA-7/IL-24 as well as naturally-occurring chemicals have also been tested using MMTV-neu models. Recent studies have shown that MMTV-neu models are useful to develop vaccines to HER2 for immunotherapy. The mouse models employing HER2/neu will be essential for future antibody or drug screenings to overcome resistance to trastuzumab or HER(2)-specific tyrosine kinase inhibitors.

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Non-HER2 signaling pathways activated in resistance to anti-HER2 therapy in breast cancer

Cited by 20 publications

References 101 publications

ESE-1 Knockdown Attenuates Growth in Trastuzumab-resistant HER2+ Breast Cancer Cells

ESE-1 Knockdown Attenuates Growth in Trastuzumab-resistant HER2+ Breast Cancer Cells

STAT3 activation confers trastuzumab‐emtansine (T‐DM1) resistance in HER2‐positive breast cancer

Clinical applications of mouse models for breast cancer engaging HER2/neu

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