A role for the pseudokinase HER3 in the acquired resistance against EGFR- and HER2-directed targeted therapy

Claus, Jeroen; Patel, Gargi; Ng, Tony; Parker, Peter J.

doi:10.1042/bst20140043

Cited by 23 publications

(19 citation statements)

References 49 publications

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“…HER3 plays a major role in the survival of HER2+ breast cancers and their resistance to HER2-targeted drugs [20, 21]. It was previously shown that breast cancer cells engineered to overexpress EGFR are sensitized to DDA-induced cell death and Akt dephosphorylation [33], but differential sensitivity to DDA-mediated HER3 downregulation was not examined in that report.…”

Section: Resultsmentioning

confidence: 99%

Disulfide bond disrupting agents activate the unfolded protein response in EGFR- and HER2-positive breast tumor cells

et al. 2017

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Many breast cancer deaths result from tumors acquiring resistance to available therapies. Thus, new therapeutic agents are needed for targeting drug-resistant breast cancers. Drug-refractory breast cancers include HER2+ tumors that have acquired resistance to HER2-targeted antibodies and kinase inhibitors, and “Triple-Negative” Breast Cancers (TNBCs) that lack the therapeutic targets Estrogen Receptor, Progesterone Receptor, and HER2. A significant fraction of TNBCs overexpress the HER2 family member Epidermal Growth Factor Receptor (EGFR). Thus agents that selectively kill EGFR+ and HER2+ tumors would provide new options for breast cancer therapy. We previously identified a class of compounds we termed Disulfide bond Disrupting Agents (DDAs) that selectively kill EGFR+ and HER2+ breast cancer cells in vitro and blocked the growth of HER2+ breast tumors in an animal model. DDA-dependent cytotoxicity was found to correlate with downregulation of HER1-3 and Akt dephosphorylation. Here we demonstrate that DDAs activate the Unfolded Protein Response (UPR) and that this plays a role in their ability to kill EGFR+ and HER2+ cancer cells. The use of breast cancer cell lines ectopically expressing EGFR or HER2 and pharmacological probes of UPR revealed all three DDA responses: HER1-3 downregulation, Akt dephosphorylation, and UPR activation, contribute to DDA-mediated cytotoxicity. Significantly, EGFR overexpression potentiates each of these responses. Combination studies with DDAs suggest that they may be complementary with EGFR/HER2-specific receptor tyrosine kinase inhibitors and mTORC1 inhibitors to overcome drug resistance.

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Section: Resultsmentioning

confidence: 99%

Disulfide bond disrupting agents activate the unfolded protein response in EGFR- and HER2-positive breast tumor cells

et al. 2017

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“…The human epidermal growth factor receptor 3 (HER3 or ErbB3) has recently attracted attention as a candidate target for anticancer therapy (1,2). HER3 is involved in the development of a variety of cancer types such as prostate, breast, lung, and colorectal, as well in the resistance towards tyrosine kinase-targeted therapies (3,4). HER3 has an inactive tyrosine kinase domain, therefore its heterodimerization with other HER-family members is required for activation and signalling (5).…”

Section: Introductionmentioning

confidence: 99%

“…The preferred partner for HER3 heterodimerization is HER2 and together they form one of the most potent units in tumourigenesis that is able to activate downstream signalling pathways, such as MAPK/MEK and PI-3K/Akt (6). The role of HER3 expression in resistance to anti-HER2 therapy in breast cancer is well documented (2,3). Signalling by the HER2/HER3 heterodimer is also critical in hormone-refractory prostate cancer and it was demonstrated that blocking of heterodimerization inhibited the growth of hormonerefractory prostate cancer xenografts (7).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of a radiocobalt-labelled affibody molecule for imaging of human epidermal growth factor receptor 3 expression

Rosestedt

Andersson

Mitran

et al. 2017

International Journal of Oncology

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The human epidermal growth factor receptor 3 (HER3) is involved in the development of cancer resistance towards tyrosine kinase-targeted therapies. Several HER3‑targeting therapeutics are currently under clinical evaluation. Non-invasive imaging of HER3 expression could improve patient management. Affibody molecules are small engineered scaffold proteins demonstrating superior properties as targeting probes for molecular imaging compared with monoclonal antibodies. Feasibility of in vivo HER3 imaging using affibody molecules has been previously demonstrated. Preclinical studies have shown that the contrast when imaging using anti-HER3 affibody molecules can be improved over time. We aim to develop an agent for PET imaging of HER3 expression using the long-lived positron-emitting radionuclide cobalt-55 (55Co) (T1/2=17.5 h). A long-lived cobalt isotope 57Co was used as a surrogate for 55Co in this study. The anti-HER3 affibody molecule HEHEHE-ZHER3-NOTA was labelled with radiocobalt with high yield, purity and stability. Biodistribution of 57Co-HEHEHE-ZHER3-NOTA was measured in mice bearing DU145 (prostate carcinoma) and LS174T (colorectal carcinoma) xenografts at 3 and 24 h post injection (p.i.). Tumour-to-blood ratios significantly increased between 3 and 24 h p.i. (p<0.05). At 24 h p.i., tumour-to-blood ratios were 6 for DU145 and 8 for LS174T xenografts, respectively. HER3‑expressing xenografts were clearly visualized in a preclinical imaging setting already 3 h p.i., and contrast further improved at 24 h p.i. In conclusion, the radiocobalt-labelled anti-HER3 affibody molecule, HEHEHE-ZHER3-NOTA, is a promising tracer for imaging of HER3 expression in tumours.

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“…The HER2-HER3 unit activates downstream signalling pathways, such as PI-3K/Akt and MAPK/MEK and is considered as one of the most potent hetero-dimers in tumorigenesis 3 . Strong evidence points to the involvement of HER3 in various cancers, such as breast, prostate and colorectal cancer, and its role in the resistance of these tumours to receptor tyrosine kinase-targeted therapies 4 5 . In response to trastuzumab therapy in HER2 overexpressing breast cancer, HER3 can become upregulated and increase the signalling ability of HER2 as a compensation for its inhibition, which cause resistance to therapy 6 7 .…”

mentioning

confidence: 99%

Affibody-mediated PET imaging of HER3 expression in malignant tumours

Rosestedt

Andersson

Mitran

et al. 2015

Sci Rep

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Human epidermal growth factor receptor 3 (HER3) is involved in the progression of various cancers and in resistance to therapies targeting the HER family. In vivo imaging of HER3 expression would enable patient stratification for anti-HER3 immunotherapy. Key challenges with HER3-targeting are the relatively low expression in HER3-positive tumours and HER3 expression in normal tissues. The use of positron-emission tomography (PET) provides advantages of high resolution, sensitivity and quantification accuracy compared to SPECT. Affibody molecules, imaging probes based on a non-immunoglobulin scaffold, provide high imaging contrast shortly after injection. The aim of this study was to evaluate feasibility of PET imaging of HER3 expression using 68Ga-labeled affibody molecules. The anti-HER3 affibody molecule HEHEHE-Z08698-NOTA was successfully labelled with 68Ga with high yield, purity and stability. The agent bound specifically to HER3-expressing cancer cells in vitro and in vivo. At 3 h pi, uptake of 68Ga-HEHEHE-Z08698-NOTA was significantly higher in xenografts with high HER3 expression (BT474, BxPC-3) than in xenografts with low HER3 expression (A431). In xenografts with high expression, tumour-to-blood ratios were >20, tumour-to-muscle >15, and tumour-to-bone >7. HER3-positive xenografts were visualised using microPET 3 h pi. In conclusion, PET imaging of HER3 expression is feasible using 68Ga-HEHEHE-Z08698-NOTA shortly after administration.

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A role for the pseudokinase HER3 in the acquired resistance against EGFR- and HER2-directed targeted therapy

Cited by 23 publications

References 49 publications

Disulfide bond disrupting agents activate the unfolded protein response in EGFR- and HER2-positive breast tumor cells

Disulfide bond disrupting agents activate the unfolded protein response in EGFR- and HER2-positive breast tumor cells

Evaluation of a radiocobalt-labelled affibody molecule for imaging of human epidermal growth factor receptor 3 expression

Affibody-mediated PET imaging of HER3 expression in malignant tumours

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