Emerging anti-cancer antibodies and combination therapies targeting HER3/ERBB3

Gaborit, Nadège; Lindzen, Moshit; Yarden, Yosef

doi:10.1080/21645515.2015.1102809

Cited by 45 publications

(36 citation statements)

References 155 publications

(184 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This list predicts that yet unknown kinase domain mutations will show similar sensitivities. Nevertheless, co‐administration of three different mAbs is expected to cause some adverse effects, such as skin and gastrointestinal tract toxicities (Kol et al , ; Gaborit et al , ).…”

Section: Discussionmentioning

confidence: 99%

An oligoclonal antibody durably overcomes resistance of lung cancer to third‐generation EGFR inhibitors

et al. 2017

Self Cite

View full text Add to dashboard Cite

Epidermal growth factor receptor (EGFR) mutations identify patients with lung cancer who derive benefit from kinase inhibitors. However, most patients eventually develop resistance, primarily due to the T790M second‐site mutation. Irreversible inhibitors (e.g., osimertinib/AZD9291) inhibit T790M‐EGFR, but several mechanisms, including a third‐site mutation, C797S, confer renewed resistance. We previously reported that a triple mixture of monoclonal antibodies, 3×mAbs, simultaneously targeting EGFR, HER2, and HER3, inhibits T790M‐expressing tumors. We now report that 3×mAbs, including a triplet containing cetuximab and trastuzumab, inhibits C797S‐expressing tumors. Unlike osimertinib, which induces apoptosis, 3×mAbs promotes degradation of the three receptors and induces cellular senescence. Consistent with distinct mechanisms, treatments combining 3×mAbs plus sub‐inhibitory doses of osimertinib synergistically and persistently eliminated tumors. Thus, oligoclonal antibodies, either alone or in combination with kinase inhibitors, might preempt repeated cycles of treatment and rapid emergence of resistance.

show abstract

Section: Discussionmentioning

confidence: 99%

An oligoclonal antibody durably overcomes resistance of lung cancer to third‐generation EGFR inhibitors

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…HER3/ErbB3 is a member of the human epidermal growth factor receptor (EGFR) family [1] and HER3 expression has been correlated with tumor progression and reduction of patient survival in pancreatic, breast, ovarian and gastric cancer, in head and neck squamous cell carcinoma and in melanoma [2–7]. Therefore, much effort is currently focused on the development of anti-HER3 therapeutic antibodies for cancer treatment [8, 9].…”

Section: Introductionmentioning

confidence: 99%

The anti-HER3 (ErbB3) therapeutic antibody 9F7-F11 induces HER3 ubiquitination and degradation in tumors through JNK1/2- dependent ITCH/AIP4 activation

Clorennec

Lazrek

Dubreuil³

et al. 2016

Oncotarget

View full text Add to dashboard Cite

We characterized the mechanism of action of the neuregulin-non-competitive anti-HER3 therapeutic antibody 9F7-F11 that blocks the PI3K/AKT pathway, leading to cell cycle arrest and apoptosis in vitro and regression of pancreatic and breast cancer in vivo. We found that 9F7-F11 induces rapid HER3 down-regulation. Specifically, 9F7-F11-induced HER3 ubiquitination and degradation in pancreatic, breast and prostate cancer cell lines was driven mainly by the itchy E3 ubiquitin ligase (ITCH/AIP4). Overexpression of the ITCH/AIP4 inhibitor N4BP1 or small-interfering RNA-mediated knockdown of ITCH/AIP4 inhibited HER3 ubiquitination/degradation and PI3K/AKT signaling blockade induced by 9F7-F11. Moreover, 9F7-F11-mediated JNK1/2 phosphorylation led to ITCH/AIP4 activation and recruitment to HER3 for receptor ubiquitination and degradation. ITCH/AIP4 activity was activated by the deubiquitinases USP8 and USP9X, as demonstrated by RNA interference. Taken together, our results suggest that 9F7-F11-induced HER3 ubiquitination and degradation in cancer cells mainly occurs through JNK1/2-dependent ITCH/AIP4 activation.

show abstract

“…Enhanced HRG/ErbB3 signaling has also been implicated in resistance to anticancer agents, including antiestrogens, ErbB tyrosine kinase inhibitors, and taxanes, and adaptive responses leading to drug resistance involve reprogramming of the kinome through reactivation of an HRG/ErbB3 axis (23)(24)(25)(26)(27)(28)(29). Consistent with the critical role of ErbB3 activation in breast cancer and other cancers, several targeted approaches designed to block HRG/ErbB3 are currently under clinical evaluation (30)(31)(32). Despite the recognized complexities of ErbB4 signaling and controversies regarding its role in cancers, this HRG receptor has been also implicated in breast tumorigenesis (33,34).…”

mentioning

confidence: 99%

Heregulin/ErbB3 Signaling Enhances CXCR4-Driven Rac1 Activation and Breast Cancer Cell Motility via Hypoxia-Inducible Factor 1α

López‐Haber

Barrio-Real

Casado‐Medrano

et al. 2016

Molecular and Cellular Biology

View full text Add to dashboard Cite

The growth factor heregulin (HRG), a ligand of ErbB3 and ErbB4 receptors, contributes to breast cancer development and the promotion of metastatic disease, and its expression in breast tumors has been associated with poor clinical outcome and resistance to therapy. In this study, we found that breast cancer cells exposed to sustained HRG treatment show markedly enhanced Rac1 activation and migratory activity in response to the CXCR4 ligand SDF-1/CXCL12, effects mediated by P-Rex1, a Rac-guanine nucleotide exchange factor (GEF) aberrantly expressed in breast cancer. Notably, HRG treatment upregulates surface expression levels of CXCR4, a G protein-coupled receptor (GPCR) implicated in breast cancer metastasis and an indicator of poor prognosis in breast cancer patients. A detailed mechanistic analysis revealed that CXCR4 upregulation and sensitization of the Rac response/motility by HRG are mediated by the transcription factor hypoxia-inducible factor 1␣ (HIF-1␣) via ErbB3 and independently of ErbB4. HRG caused prominent induction in the nuclear expression of HIF-1␣, which transcriptionally activates the CXCR4 gene via binding to a responsive element located in positions ؊1376 to ؊1372 in the CXCR4 promoter, as revealed by mutagenesis analysis and chromatin immunoprecipitation (ChIP). Our results uncovered a novel function for ErbB3 in enhancing breast cancer cell motility and sensitization of the P-Rex1/Rac1 pathway through HIF-1␣-mediated transcriptional induction of CXCR4. E rbB receptors are known to play key roles in cell proliferation, survival, and motility and have been widely implicated in the initiation and progression of cancer. Members of this family of transmembrane tyrosine kinases include epidermal growth factor receptors (EGFR) (ErbB1/HER1), ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4. Ligands with distinctive affinities for ErbB receptors promote their homo-and heterodimerization, leading to stimulation of intrinsic tyrosine kinase activity; recruitment of adaptors and effectors to autophosphorylated tyrosine sites; and activation of key signaling cascades, namely, the phosphatidylinositol-3 kinase (PI3K)/Akt, extracellular signal regulated kinase (ERK), and protein kinase C (PKC) pathways (1-4). Dysregulation of the ErbB signaling pathway is a common alteration in human cancer, and it occurs largely as a consequence of gain-offunction mutations (e.g., EGFR); gene amplification (e.g., ErbB2); and/or overexpression of ErbB ligands, such as EGF and transforming growth factor alpha (TGF␣) (EGFR ligands) and heregulin-1/neuregulin-1 (HRG) (ErbB3/ErbB4 ligand) (5-10).ErbB3 has been shown to be crucially important in breast cancer progression. This receptor is catalytically inactive, and hence, its signaling capacity depends entirely on dimerization with other catalytically competent ErbB partners. ErbB2, the only orphan member of the ErbB receptor family, is the preferred dimerization partner for ErbB3, and the ErbB2/ErbB3 heterodimer, which signals preferentially through PI3K, is regarded as a major oncog...

show abstract

Emerging anti-cancer antibodies and combination therapies targeting HER3/ERBB3

Cited by 45 publications

References 155 publications

An oligoclonal antibody durably overcomes resistance of lung cancer to third‐generation EGFR inhibitors

An oligoclonal antibody durably overcomes resistance of lung cancer to third‐generation EGFR inhibitors

The anti-HER3 (ErbB3) therapeutic antibody 9F7-F11 induces HER3 ubiquitination and degradation in tumors through JNK1/2- dependent ITCH/AIP4 activation

Heregulin/ErbB3 Signaling Enhances CXCR4-Driven Rac1 Activation and Breast Cancer Cell Motility via Hypoxia-Inducible Factor 1α

Contact Info

Product

Resources

About