Expression of TweakR in breast cancer and preclinical activity of enavatuzumab, a humanized anti-TweakR mAb

• Published in: Journal of cancer research and clinical oncology Vol. 139; no. 2; pp. 315 - 325
• Main Authors: Chao, Debra T., Su, Mian, Tanlimco, Sonia, Sho, Mien, Choi, Donghee, Fox, Mel, Ye, Shiming, Hsi, Eric D., Durkin, Lisa, Yin, Johnny, Zhang, Yongke, Kim, Han, Starling, Gary C., Culp, Patricia A.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.02.2013; Springer; Springer Nature B.V
• Subjects: Animals; Antibodies, Monoclonal, Humanized - administration & dosage; Antibodies, Monoclonal, Humanized - pharmacology; Antibodies, Monoclonal, Humanized - therapeutic use; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Breast cancer; Cancer Research; Carcinoma, Ductal, Breast - drug therapy; Carcinoma, Ductal, Breast - genetics; Carcinoma, Ductal, Breast - metabolism; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation; Cytokines; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Synergism; Female; Gene Expression; Gynecology. Andrology. Obstetrics; Hematology; Humans; Internal Medicine; Mammary gland diseases; Medical sciences; Medicine; Medicine & Public Health; Mice; Monoclonal antibodies; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Invasiveness - genetics; Oncology; Original Paper; Pharmacology. Drug treatments; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Receptors, Tumor Necrosis Factor - genetics; Receptors, Tumor Necrosis Factor - metabolism; Trastuzumab; Tumors; TWEAK Receptor; Xenograft Model Antitumor Assays; Breast cancer; Fn14; TweakR; Antibody; Breast disease; Preclinical trial; Malignant tumor; Monoclonal antibody; Gene expression; Biological activity; Enavatuzumab; Mammary gland diseases; TWEAK receptor; Cancer
• ISSN: 0171-5216; 1432-1335
• DOI: 10.1007/s00432-012-1332-x

Background The receptor for the cytokine TWEAK (TweakR) is a cell surface member of the tumor necrosis factor receptor superfamily with diverse biological roles. TNFRSF family members are appealing therapeutic targets in oncology due to their aberrant expression and function in tumor cells. The goal of the current study was to examine the potential of TweakR as a therapeutic target in breast cancer. Methods Expression of TweakR in primary breast cancer tissues and metastases was characterized using immunohistochemistry. To determine the functional relevance of TweakR, breast cancer cell lines were treated in vitro and in vivo with enavatuzumab, a humanized mAb against TweakR. Results Overexpression of TweakR was observed in infiltrating tumors compared to normal adjacent breast tissues, and strong staining of TweakR was observed in all subtypes of invasive ductal breast cancer. In addition, a positive correlation of TweakR and HER2 expression and co-localization were observed, irrespective of ER status. TweakR expression was also observed in bone metastasis samples from primary breast cancer but rarely in benign tumors. Enavatuzumab inhibited the in vitro growth of TweakR-expressing breast cancer cell lines, and this activity was augmented by cross-linking the mAb. In addition, enavatuzumab significantly inhibited the in vivo growth of multiple breast cancer xenograft models including a model of metastasis. Conclusions TweakR is highly expressed in all subtypes of invasive ductal breast cancer, and enavatuzumab administration exhibited a dose-dependent inhibition of primary tumor growth and lung metastasis and enhanced the antitumor activity of several chemotherapy agents currently used to treat breast cancer. These data provide the rationale to evaluate enavatuzumab as a potential therapy for the treatment of breast cancer.