Genetic and Chemical Targeting of Epithelial-Restricted with Serine Box Reduces EGF Receptor and Potentiates the Efficacy of Afatinib

Zhang, Manchao; Taylor, Christopher E.; Piao, Longzhu; Datta, Jharna; Bruno, Paul A.; Bhave, Sanjay L.; Su, Ti‐Zhi; Lang, James C.; Xie, Xiujie; Teknos, Theodoros N.; Mapp, Anna K.; Pan, Quintin

doi:10.1158/1535-7163.mct-12-1110

Cited by 6 publications

(10 citation statements)

References 24 publications

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“…To date, 20 manuscripts have been reported in the peer-reviewed literature assessing HER2 expression in HNSCC tumors (14-33). Six papers have evaluated HER2 targeting in HNSCC preclinical models, and 2 trials have been completed and reported using HER2 inhibitors for this malignancy (18, 34-40). In this review, we will evaluate the preclinical and clinical data implicating HER2 as a therapeutic target in HNSCC.…”

Section: Introductionmentioning

confidence: 99%

HER2 as a Therapeutic Target in Head and Neck Squamous Cell Carcinoma

Pollock

Grandis

2015

Clinical Cancer Research

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The majority of patients with head and neck squamous cell carcinoma (HNSCC) present with advanced-stage disease. Current standard of care is surgery followed by adjuvant radiation therapy with or without chemotherapy or chemoradiation alone. The addition of cetuximab for the treatment of patients with locally advanced or recurrent/metastatic HNSCC has improved overall survival and locoregional control; however, responses are often modest, and treatment resistance is common. A variety of therapeutic strategies are being explored to overcome cetuximab resistance by blocking candidate proteins implicated in resistance mechanisms such as HER2. Several HER2 inhibitors are in clinical development for HNSCC, and HER2-targeted therapy has been approved for several cancers. This review focuses on the biology of HER2, its role in cancer development, and the rationale for clinical investigation of HER2 targeting in HNSCC.

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Section: Introductionmentioning

confidence: 99%

HER2 as a Therapeutic Target in Head and Neck Squamous Cell Carcinoma

Pollock

Grandis

2015

Clinical Cancer Research

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“…Down-regulation of ESX or EGFR induced a pleotropic anti-tumor effect in HNSCC (16). Our results showed that rescue of miR-124 to physiologic levels in HNSCC cells reduced ESX and EGFR.…”

Section: Resultsmentioning

confidence: 99%

“…These observations suggest that the predominant mechanism for EGFR dysregulation in HNSCC may be at the transcriptional level. Recent work from our laboratory revealed ESX as a transcription factor that modulates EGFR at the transcriptional level (16). Genetic ablation of ESX in ESX high /EGFR high HNSCC cells resulted in a reduced EGFR promoter activity and mRNA expression (16).…”

Section: Introductionmentioning

confidence: 99%

“…Recent work from our laboratory revealed ESX as a transcription factor that modulates EGFR at the transcriptional level (16). Genetic ablation of ESX in ESX high /EGFR high HNSCC cells resulted in a reduced EGFR promoter activity and mRNA expression (16). Our work showed that ESX is upstream of EGFR to provide a novel molecular mechanism to account for EGFR dysregulation in HNSCC.…”

Section: Introductionmentioning

confidence: 99%

“…There is evidence that ESX is elevated and modulates EGFR in HNSCC (16). However, a mechanism for ESX dysregulation in HNSCC remains to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

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miR-124 Regulates the Epithelial-Restricted with Serine Box/Epidermal Growth Factor Receptor Signaling Axis in Head and Neck Squamous Cell Carcinoma

Zhang

Piao

Datta

et al. 2015

Molecular Cancer Therapeutics

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Epithelial-restricted with serine box (ESX), a member of the ETS transcription factor family, is elevated and regulates epidermal growth factor receptor (EGFR) in head and neck squamous cell carcinoma (HNSCC). However, the molecular mechanisms that contribute to ESX dysregulation remains to be elucidated. In this study, in silico analysis of the 3′-untranslated region (UTR) of ESX predicted two miR-124 binding sites. Delivery of miR-124 inhibited the 3′UTR ESX-driven reporter activity by 50% (p<0.05) confirming ESX as a direct target of miR-124. Loss of miR-124 was found to a frequent event in HNSCC. miR-124 expression was significantly depleted in the primary tumor compared to matched normal tissue in 100% (12/12) of HNSCC patients; relative mean miR-124 expression of 0.01197 and 0.00118 (p<0.001, n=12) in matched normal adjacent tissue and primary HNSCC tumor, respectively. Over-expression of miR-124 decreased ESX and EGFR levels in miR-124low/ESXhigh/EGFRhigh SCC15 HNSCC cells and reduced cell invasion, migration, proliferation and colony formation. SCC15 cells with miR-124 restoration were less tumorigenic in vivo than miR-control SCC15 cells (70% inhibition, p<0.01). Restoration of miR-124 in SCC15 cells enhanced the anti-proliferative efficacy of the EGFR/Her2 TKIs. Furthermore, recapitulation of EGFR in miR-124 over-expressing SCC15 cells was sufficient to completely block the anti-proliferative effects of lapatinib and afatinib. Taken together, our work provides intriguing evidence that miR-124 is a novel therapeutic approach to reduce ESX/EGFR and may be a tractable strategy to enhance the response rate of HNSCC patients to current anti-EGFR/Her2 therapies.

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A comprehensive review of the preclinical efficacy profile of the ErbB family blocker afatinib in cancer

Modjtahedi

Cho

Michel

et al. 2014

Naunyn-Schmiedeberg's Arch Pharmacol

102

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Afatinib (also known as BIBW 2992) has recently been approved in several countries for the treatment of a distinct type of epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer. This manuscript comprehensively reviews the preclinical data on afatinib, an irreversible inhibitor of the tyrosine kinase activity of members of the epidermal growth factor receptor family (ErbB) including EGFR, HER2 and ErbB4. Afatinib covalently binds to cysteine 797 of the EGFR and the corresponding cysteines 805 and 803 in HER2 and ErbB4, respectively. Such covalent binding irreversibly inhibits the tyrosine kinase activity of these receptors, resulting in reduced auto-and transphosphorylation within the ErbB dimers and inhibition of important steps in the signal transduction of all ErbB receptor family members. Afatinib inhibits cellular growth and induces apoptosis in a wide range of cells representative for non-small cell lung cancer, breast cancer, pancreatic cancer, colorectal cancer, head and neck squamous cell cancer and several other cancer types exhibiting abnormalities of the ErbB network. This translates into tumour shrinkage in a variety of in vivo rodent models of such cancers. Afatinib retains inhibitory effects on signal transduction and in vitro and in vivo cancer cell growth in tumours resistant to reversible EGFR inhibitors, such as those exhibiting the T790M mutations. Several combination treatments have been explored to prevent and/or overcome development of resistance to afatinib, the most promising being those with EGFR-or HER2-targeted antibodies, other tyrosine kinase inhibitors or inhibitors of downstream signalling molecules.

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Genetic and Chemical Targeting of Epithelial-Restricted with Serine Box Reduces EGF Receptor and Potentiates the Efficacy of Afatinib

Cited by 6 publications

References 24 publications

HER2 as a Therapeutic Target in Head and Neck Squamous Cell Carcinoma

HER2 as a Therapeutic Target in Head and Neck Squamous Cell Carcinoma

miR-124 Regulates the Epithelial-Restricted with Serine Box/Epidermal Growth Factor Receptor Signaling Axis in Head and Neck Squamous Cell Carcinoma

A comprehensive review of the preclinical efficacy profile of the ErbB family blocker afatinib in cancer

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