Expression of TweakR in breast cancer and preclinical activity of enavatuzumab, a humanized anti-TweakR mAb.
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.
Discovery, GPRD, Abbott Biotherapeutics, 1500 Seaport Blvd, Redwood City, CA 94063, USA. debra.chao@abbott.com
Debra T
DT
Chao
Mian
M
Su
Sonia
S
Tanlimco
Mien
M
Sho
Donghee
D
Choi
Mel
M
Fox
Shiming
S
Ye
Eric D
ED
Hsi
Lisa
L
Durkin
Johnny
J
Yin
Yongke
Y
Zhang
Han
H
Kim
Gary C
GC
Starling
Patricia A
PA
Culp
D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D005260:Female; D015870:Gene Expression; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D000074050:TWEAK Receptor; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; D018124:Receptors, Tumor Necrosis Factor; D000074050:TWEAK Receptor; D000068878:Trastuzumab; C000613299:Tnfrsf12a protein, mouse; C578859:enavatuzumab