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Author Notes:

Corresponding Authors: Nabil F. Saba, Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, 1365-C Clifton Road, Suite C3086, Atlanta, GA 30322. Phone: 404-778-1900; Fax: 404-686-4330; nfsaba@emory.edu; Zhuo G. Chen, Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, 1365-C Clifton Road, Suite C3086, Atlanta, GA 30322. Phone: 404-778-3977; Fax: 404-778-5520; gzchen@emory.edu

We thank Dr. Anthea Hammond for her critical reading and editing of the manuscript.

G. Garcia and G. MacBeath are employees and stockholders of Merrimack Pharmaceuticals.

Subject:

Research Funding:

This study was supported by funding from Merrimack Pharmaceuticals Inc. to G.Z. Chen and N.F. Saba and partially by grant from the Specialized Program of Excellence (SPORE) in Head and Neck Cancer (P50CA128613) to D.M. Shin.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Oncology
  • TYROSINE KINASE INHIBITORS
  • FACTOR-RECEPTOR
  • ANTITUMOR-ACTIVITY
  • CANCER-CELLS
  • HUMAN-PAPILLOMAVIRUS
  • ACQUIRED-RESISTANCE
  • MOLECULAR TARGET
  • PLUS CETUXIMAB
  • BREAST-CANCER
  • EGFR

Combination of Anti-HER3 Antibody MM-121/SAR256212 and Cetuximab Inhibits Tumor Growth in Preclinical Models of Head and Neck Squamous Cell Carcinoma

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Journal Title:

Molecular Cancer Therapeutics

Volume:

Volume 13, Number 7

Publisher:

, Pages 1826-1836

Type of Work:

Article | Post-print: After Peer Review

Abstract:

The EGFR monoclonal antibody cetuximab is the only approved targeted agent for treating head and neck squamous cell carcinoma (HNSCC). Yet resistance to cetuximab has hindered its activity in this disease. Intrinsic or compensatory HER3 signaling may contribute to cetuximab resistance. To investigate the therapeutic benefit of combining MM-121/SAR256212, an anti-HER3 monoclonal antibody, with cetuximab in HNSCC, we initially screened 12 HNSCC cell lines for total and phosphorylated levels of the four HER receptors. We also investigated the combination of MM-121 with cetuximab in preclinical models of HNSCC. Our results revealed that HER3 is widely expressed and activated in HNSCC cell lines. MM-121 strongly inhibited phosphorylation of HER3 and AKT. When combined with cetuximab, MM-121 exerted a more potent antitumor activity through simultaneously inhibiting the activation of HER3 and EGFR and consequently the downstream PI3K/AKT and ERK pathways in vitro. Both high and low doses of MM-121 in combination with cetuximab significantly suppressed tumor growth in xenograft models and inhibited activations of HER3, EGFR, AKT, and ERK in vivo. Our work is the first report on this new combination in HNSCC and supports the concept that HER3 inhibition may play an important role in future therapy of HNSCC. Our results open the door for further mechanistic studies to better understand the role of HER3 in resistance to EGFR inhibitors in HNSCC.

Copyright information:

©2014 AACR

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