Targeting of the HER2/HER3 signaling axis overcomes ligand-mediated resistance to trastuzumab in HER2-positive breast cancer.
Animals
Antineoplastic Agents, Immunological
/ pharmacology
Antineoplastic Combined Chemotherapy Protocols
/ adverse effects
Breast Neoplasms
/ drug therapy
Cell Line, Tumor
Cell Survival
/ drug effects
Disease Models, Animal
Drug Resistance, Neoplasm
/ drug effects
Female
Humans
Ligands
Mice
Neuregulin-1
/ pharmacology
Receptor, ErbB-2
/ metabolism
Receptor, ErbB-3
/ metabolism
Signal Transduction
/ drug effects
Trastuzumab
/ pharmacology
Xenograft Model Antitumor Assays
heregulin (HRG)
human epidermal growth factor receptor 2 (HER2)
human epidermal growth factor receptor 3 (HER3)
neuregulin (NRG)
patritumab (U3-1287)
Journal
Cancer medicine
ISSN: 2045-7634
Titre abrégé: Cancer Med
Pays: United States
ID NLM: 101595310
Informations de publication
Date de publication:
03 2019
03 2019
Historique:
received:
03
10
2018
revised:
17
12
2018
accepted:
08
01
2019
pubmed:
1
2
2019
medline:
17
4
2020
entrez:
1
2
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30701699
doi: 10.1002/cam4.1995
pmc: PMC6434202
doi:
Substances chimiques
Antineoplastic Agents, Immunological
0
Ligands
0
Neuregulin-1
0
ERBB2 protein, human
EC 2.7.10.1
ERBB3 protein, human
EC 2.7.10.1
Receptor, ErbB-2
EC 2.7.10.1
Receptor, ErbB-3
EC 2.7.10.1
Trastuzumab
P188ANX8CK
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1258-1268Informations de copyright
© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
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