Cited by 1,858HER2/EGFR in Cancer ResearchPI3K/AKT/mTOR signaling in cancerBreast Cancer Treatment Studies

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PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients

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Nagata, Yoichi, Lan, Keng-Hsueh, Zhou, Xiaoyan, Tan, Ming, Esteva, Francisco J., Sahin, Aysegul A., Klos, Kristine S., Li, Ping, Monia, Brett P., Nguyen, Nina T., Hortobagyi, Gabriel N., Hung, Mien-Chie, Yu, Dihua·2004·Cancer Cell

DOI 10.1016/j.ccr.2004.06.022

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Abstract

The ErbB2-targeting antibody, trastuzumab (Herceptin), has remarkable therapeutic efficacy in certain patients with ErbB2-overexpressing tumors. The overall trastuzumab response rate, however, is limited and what determines trastuzumab response is poorly understood. Here we report that PTEN activation contributes to trastuzumab's antitumor activity. Trastuzumab treatment quickly increased PTEN membrane localization and phosphatase activity by reducing PTEN tyrosine phosphorylation via Src inhibition. Reducing PTEN in breast cancer cells by antisense oligonucleotides conferred trastuzumab resistance in vitro and in vivo. Patients with PTEN-deficient breast cancers had significantly poorer responses to trastuzumab-based therapy than those with normal PTEN. Thus, PTEN deficiency is a powerful predictor for trastuzumab resistance. Additionally, PI3K inhibitors rescued PTEN loss-induced trastuzumab resistance, suggesting that PI3K-targeting therapies could overcome this resistance.

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Authors: Nagata, Y., Lan, K.-H., Zhou, X., Tan, M., Esteva, F. J., Sahin, A. A., Klos, K. S., Li, P., Monia, B. P., Nguyen, N. T., Hortobagyi, G. N., Hung, M.-C., & Yu, D.
Affiliations: The University of Texas MD Anderson Cancer Center (US)
Ionis Pharmaceuticals (United States) (US)
Corresponding author: Yu, Dihua
ORCID: Lan, Keng-Hsueh
Zhou, Xiaoyan
Tan, Ming
Esteva, Francisco J.
Li, Ping
Monia, Brett P.
Hung, Mien-Chie
Yu, Dihua
Venue: Cancer Cell
Publisher: Elsevier BV
Published: 2004-08
Volume: 6
Issue: 2
Pages: 117-127
ISSN: 1535-6108 (ISSN-L)
DOI: 10.1016/j.ccr.2004.06.022
OpenAlex: W2059411043
Cited by: 1,858
References: 70
Citations by year: 2026: 19 · 2025: 29 · 2024: 35 · 2023: 82 · 2022: 52 · 2021: 50 · 2020: 60 · 2019: 56 · 2018: 66 · 2017: 68 · 2016: 88 · 2015: 109 · 2014: 119 · 2013: 125 · 2012: 123
FWCI: 43.34
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 3272 d)
Locations: Cancer Cell (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5r01ca060488-09)
National Cancer Institute (P01CA099031, 2R01-CA60488, P30CA016672)
Topics: Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
Keywords: PTEN, trastuzumab, trastuzumab resistance, ERBB2, HER2-positive breast cancer, Src kinase inhibition, PI3K inhibitors, predictive biomarkers, antisense oligonucleotides
MeSH terms: Trastuzumab, Phosphoinositide-3 Kinase Inhibitors, Animals, Antibodies, Monoclonal, Antineoplastic Agents, Breast Neoplasms, Enzyme Activation, Enzyme Inhibitors, Female, Humans, Mice, Nude, Neoplasm Transplantation, Phosphoric Monoester Hydrolases, Proto-Oncogene Proteins, Genes, Tumor Suppressor, Oligonucleotides, Antisense, Protein Serine-Threonine Kinases, Erb-b2 Receptor Tyrosine Kinases, Drug Resistance, Neoplasm, src-Family Kinases, Phosphatidylinositol 3-Kinases, Tumor Suppressor Proteins, Cell Line, Tumor, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, Mice, Antibodies, Monoclonal, Humanized

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PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients

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