Regulation of Heparin-Binding EGF-Like Growth Factor by miR-212 and Acquired Cetuximab-Resistance in Head and Neck Squamous Cell Carcinoma

Hatakeyama, Hyōe; Cheng, Haixia; Wirth, Pamela S.; Counsell, Ashley; Marcrom, S.; Wood, C. Burton; Pohlmann, Paula R.; Gilbert, Jill; Murphy, Barbara A.; Yarbrough, Wendell G.; Wheeler, Deric L.; Harari, Paul M.; Guo, Yan; Shyr, Yu; Slebos, Robbert J.C.; Chung, Christine H.

doi:10.1371/journal.pone.0012702

Cited by 129 publications

(123 citation statements)

References 47 publications

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“…1). Our comprehensive analysis of how both low-and high-affinity EGFR ligands and ligand mixtures impact monoclonal antibody antagonism confirms and extends prior work with single ligands and cetuximab (19)(20)(21).…”

Section: Discussionsupporting

confidence: 80%

“…For example, preclinical studies show that upregulation of TGFa or HB-EGF can maintain EGFR signaling and promote cetuximab resistance (19)(20)(21), whereas heregulin and hepatocyte growth factor can induce cetuximab resistance via bypass of EGFR (22,23). In contrast, AREG upregulation correlates with sensitivity to cetuximab and EGFR TKIs in vitro (24,25).…”

Section: Introductionmentioning

confidence: 99%

“…In colorectal cancer tumors, upregulation of the low-affinity EGFR ligands AREG and EREG occurs, and several clinical studies suggest that high levels of their mRNAs predict clinical benefit with cetuximab treatment (26)(27)(28)(29). Less is known about the possible predictive nature of highaffinity EGFR ligand expression; however, several groups have reported high-affinity ligand expression (RNA and protein) in tumors and serum (19,26,(30)(31)(32)(33)(34). Together, these studies highlight the capacity of EGFR ligands to modulate sensitivity to EGFR-targeting antibodies and potential as predictive markers in the clinic.…”

Section: Introductionmentioning

confidence: 99%

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Enhanced Targeting of the EGFR Network with MM-151, an Oligoclonal Anti-EGFR Antibody Therapeutic

Kearns

Bukhalid

Sevecka

et al. 2015

Molecular Cancer Therapeutics

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Although EGFR is a validated therapeutic target across multiple cancer indications, the often modest clinical responses to current anti-EGFR agents suggest the need for improved therapeutics. Here, we demonstrate that signal amplification driven by highaffinity EGFR ligands limits the capacity of monoclonal anti-EGFR antibodies to block pathway signaling and cell proliferation and that these ligands are commonly coexpressed with low-affinity EGFR ligands in epithelial tumors. To develop an improved antibody therapeutic capable of overcoming high-affinity ligand-mediated signal amplification, we used a network biology approach comprised of signaling studies and computational modeling of receptor-antagonist interactions. Model simulations suggested that an oligoclonal antibody combination may overcome signal amplification within the EGFR:ERK pathway driven by all EGFR ligands. Based on this, we designed MM-151, a combination of three fully human IgG1 monoclonal antibodies that can simultaneously engage distinct, nonoverlapping epitopes on EGFR with subnanomolar affinities. In signaling studies, MM-151 antagonized high-affinity EGFR ligands more effectively than cetuximab, leading to an approximately 65-fold greater decrease in signal amplification to ERK. In cell viability studies, MM-151 demonstrated antiproliferative activity against high-affinity EGFR ligands, either singly or in combination, while cetuximab activity was largely abrogated under these conditions. We confirmed this finding both in vitro and in vivo in a cell line model of autocrine high-affinity ligand expression. Together, these preclinical studies provide rationale for the clinical study of MM-151 and suggest that high-affinity EGFR ligand expression may be a predictive response marker that distinguishes MM-151 from other anti-EGFR therapeutics.

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Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Enhanced Targeting of the EGFR Network with MM-151, an Oligoclonal Anti-EGFR Antibody Therapeutic

Kearns

Bukhalid

Sevecka

et al. 2015

Molecular Cancer Therapeutics

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“…Pre-clinical data suggested that inhibition of EGFR, HER2, and HER3 by combined treatment with lapatinib, trastuzumab and U3-1287 showed maximum effect in trastuzumab-resistant HER2-overexpressing breast cancer ( Figure 5A). It has been exhibited that cetuximab-resistant clones have increased not only EGFR, HER2, HER3, and HER4, but also other receptor tyrosine kinases (RTKs) such as cMET, AXL, and IGF1R (13,45,46). Recently, mutations in the genes encoding other RTKs, such as FGFR1 or PDGFRA were found in CRC PDX models with intrinsic resistance to cetuximab (47).…”

Section: Discussionmentioning

confidence: 99%

Targeting the HER family with Pan-HER effectively overcomes resistance to cetuximab

Iida¹,

Bahrar²,

Brand³

et al. 2016

European Journal of Cancer

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“…Examination of an expression dataset of cetuximabsensitive and cetuximab-resistant HNSCC cell lines showed that PTPRS expression was significantly lower in resistant cells (P = 6 × 10 −4 ) (Fig. 4C) (48). Unfortunately, expression datasets from patients with tyrosine kinase inhibitor (TKI)-sensitive and -resistant HNSCC and lung tumors are not currently available for our analysis.…”

Section: Protein Tyrosine Phosphatase Receptor S (Ptprs) Is Frequentlymentioning

confidence: 99%

Genomic dissection of the epidermal growth factor receptor (EGFR)/PI3K pathway reveals frequent deletion of the EGFR phosphatase PTPRS in head and neck cancers

Morris¹,

Taylor²,

Bivona³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Activation of the PI3K and epidermal growth factor receptor (EGFR) pathway is able to drive oncogenesis in multiple human cancers, including head and neck squamous cell carcinoma. Targeted agents such as cetuximab and erlotinib are currently used in patients with head and neck squamous cell carcinoma, but, in this disease, the genomic alterations that cause pathway activation and determine response to pharmacologic inhibition remain ill-defined. Here, we present a detailed dissection of the EGFR/PI3K pathway, composed of sequencing of the core pathway components, and high-resolution genomic copy number assessment. Mutations were found in PIK3CA (6%), but no point mutations were observed in other pathway genes such as PTEN and EGFR . In contrast, we observed frequent copy number alterations of genes in the pathway, including PIK3CA , EGFR , protein tyrosine phosphatase receptor S ( PTPRS ), and RICTOR . In total, activating genetic pathway alterations were identified in 74% of head and neck tumors. Importantly, intragenic microdeletions of the EGFR phosphatase PTPRS were frequent (26%), identifying this gene as a target of 19p13 loss. PTPRS loss promoted EGFR/PI3K pathway activation, modulated resistance to EGFR inhibition, and strongly determined survival in lung cancer patients with activating EGFR mutations. These findings have important implications for our understanding of head and neck cancer tumorigenesis and for the use of targeted agents for this malignancy.

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Regulation of Heparin-Binding EGF-Like Growth Factor by miR-212 and Acquired Cetuximab-Resistance in Head and Neck Squamous Cell Carcinoma

Cited by 129 publications

References 47 publications

Enhanced Targeting of the EGFR Network with MM-151, an Oligoclonal Anti-EGFR Antibody Therapeutic

Enhanced Targeting of the EGFR Network with MM-151, an Oligoclonal Anti-EGFR Antibody Therapeutic

Targeting the HER family with Pan-HER effectively overcomes resistance to cetuximab

Genomic dissection of the epidermal growth factor receptor (EGFR)/PI3K pathway reveals frequent deletion of the EGFR phosphatase PTPRS in head and neck cancers

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