Targeting of the HER2/HER3 signaling axis overcomes ligand‐mediated resistance to trastuzumab in HER2‐positive breast cancer

Autor: Naoki Takegawa, Hidetoshi Hayashi, Hisato Kawakami, Junji Tsurutani, Junko Tanizaki, Kazuhiko Nakagawa, Kimio Yonesaka, Satomi Watanabe, Masayuki Takeda, Koji Haratani, Yoshikane Nonagase
Rok vydání: 2019
Předmět:
0301 basic medicine
Cancer Research
Patritumab
Receptor
ErbB-3
Cell Survival
Receptor
ErbB-2
Neuregulin-1
Breast Neoplasms
Ligands
Mice
03 medical and health sciences
Antineoplastic Agents
Immunological
0302 clinical medicine
Breast cancer
human epidermal growth factor receptor 2 (HER2)
Trastuzumab
Cell Line
Tumor
Antineoplastic Combined Chemotherapy Protocols
medicine
Animals
Humans
neuregulin (NRG)
Radiology
Nuclear Medicine and imaging
skin and connective tissue diseases
Clonogenic assay
neoplasms
Protein kinase B
Original Research
Cancer Biology
business.industry
medicine.disease
Xenograft Model Antitumor Assays
heregulin (HRG)
Blockade
Disease Models
Animal
030104 developmental biology
human epidermal growth factor receptor 3 (HER3)
patritumab (U3‐1287)
Oncology
Drug Resistance
Neoplasm
SKBR3
030220 oncology & carcinogenesis
Cancer research
Female
Pertuzumab
business
Signal Transduction
medicine.drug
Zdroj: Cancer Medicine
ISSN: 2045-7634
Popis: HER2‐targeted therapy, especially the anti‐HER2 antibody trastuzumab, is standard for HER2‐positive breast cancer; however, its efficacy is limited in a subpopulation of patients. HER3 ligand (heregulin)‐dependent HER2‐HER3 interactions play a critical role in the evasion of apoptosis and are therefore a target for oncotherapy to treat HER2‐positive breast cancer. The anti‐HER2 antibody pertuzumab and anti‐HER3 antibody patritumab both target this heregulin–HER3‐HER2 complex in different ways. This study examined the anticancer efficacy of dual HER2 and HER3 blockade in trastuzumab‐resistant HER2‐positive breast cancer. HER2‐positive SKBR3 or BT474 cells overexpressing heregulin (SKBR3‐HRG, BT474‐HRG) were used to evaluate the efficacy of trastuzumab, pertuzumab, and patritumab in vitro by performing cell viability, immunoblotting, and clonogenic assays. The effects of these agents were then evaluated in vivo using BT474‐HRG and an intrinsic heregulin‐expressing and HER2‐positive JIMT‐1 xenograft models. SKBR3‐HRG and BT474‐HRG cells lost sensitivity to trastuzumab, which was accompanied by Akt activation. Unexpectedly, trastuzumab in combination with pertuzumab or patritumab also showed limited efficacy toward these cells. In contrast, trastuzumab/pertuzumab/patritumab triple treatment demonstrated potent anticancer efficacy, concomitant with strong repression of Akt. Finally, in heregulin‐expressing BT474‐HRG and JIMT‐1 xenograft models, the addition of pertuzumab and patritumab to trastuzumab also enhanced antitumor efficacy leading to tumor regression. The current study found that triple blockade of HER2 and HER3 using trastuzumab, pertuzumab, and patritumab could overcome resistance to trastuzumab therapy in heregulin‐expressing and HER2‐positive breast cancer, which could be exploited clinically.
Databáze: OpenAIRE
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