Effects of HER Family-targeting Tyrosine Kinase Inhibitors on Antibody-dependent Cell-mediated Cytotoxicity in HER2-expressing Breast Cancer.
Adolescent
Adult
Aged
Antibodies, Monoclonal, Humanized
/ pharmacology
Antibody-Dependent Cell Cytotoxicity
/ drug effects
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Breast Neoplasms
/ genetics
Female
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Killer Cells, Natural
/ drug effects
Lapatinib
/ pharmacology
MCF-7 Cells
Middle Aged
Neoadjuvant Therapy
/ methods
Protein Kinase Inhibitors
/ pharmacology
RNA-Seq
Receptor, ErbB-2
/ antagonists & inhibitors
Trastuzumab
/ pharmacology
Young Adult
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
01 02 2021
01 02 2021
Historique:
received:
06
07
2020
revised:
18
09
2020
accepted:
22
10
2020
pubmed:
31
10
2020
medline:
19
1
2022
entrez:
30
10
2020
Statut:
ppublish
Résumé
Antibody-dependent cell-mediated cytotoxicity (ADCC) is one mechanism of action of the monoclonal antibody (mAb) therapies trastuzumab and pertuzumab. Tyrosine kinase inhibitors (TKIs), like lapatinib, may have added therapeutic value in combination with mAbs through enhanced ADCC activity. Using clinical data, we examined the impact of lapatinib on HER2/EGFR expression levels and natural killer (NK) cell gene signatures. We investigated the ability of three TKIs (lapatinib, afatinib, and neratinib) to alter HER2/immune-related protein levels in preclinical models of HER2-positive (HER2 Preclinical studies (proliferation assays, Western blotting, high content analysis, and flow cytometry) employed HER2 Lapatinib significantly increased membrane HER2 levels, while afatinib and neratinib significantly decreased levels in all preclinical models. Single-agent lapatinib increased HER2 or EGFR levels in 10 of 11 (91%) tumor samples. NK cell signatures increased posttherapy ( TKIs differentially alter tumor cell phenotype which can impact NK cell-mediated response to coadministered antibody therapies. mAb-induced ADCC response is relevant when rationalizing combinations for clinical investigation.
Identifiants
pubmed: 33122343
pii: 1078-0432.CCR-20-2007
doi: 10.1158/1078-0432.CCR-20-2007
pmc: PMC7854527
mid: NIHMS1641692
doi:
Substances chimiques
Antibodies, Monoclonal, Humanized
0
Protein Kinase Inhibitors
0
Lapatinib
0VUA21238F
ERBB2 protein, human
EC 2.7.10.1
Receptor, ErbB-2
EC 2.7.10.1
pertuzumab
K16AIQ8CTM
Trastuzumab
P188ANX8CK
Types de publication
Clinical Trial, Phase II
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
807-818Subventions
Organisme : NICHD NIH HHS
ID : R21 HD097472
Pays : United States
Organisme : NCI NIH HHS
ID : R33 CA173359
Pays : United States
Informations de copyright
©2020 American Association for Cancer Research.
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