Roles of BIM induction and survivin downregulation in lapatinib-induced apoptosis in breast cancer cells with HER2 amplification

Tanizaki, J; Okamoto, I; Fumita, S; Okamoto, W; Nishio, K; Nakagawa, K

doi:10.1038/onc.2011.111

Cited by 70HER2/EGFR in Cancer ResearchPI3K/AKT/mTOR signaling in cancerCell death mechanisms and regulation

Roles of BIM induction and survivin downregulation in lapatinib-induced apoptosis in breast cancer cells with HER2 amplification

Tanizaki, J, Okamoto, I, Fumita, S, Okamoto, W, Nishio, K, Nakagawa, K·2011·Oncogene

DOI 10.1038/onc.2011.111

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Abstract

Lapatinib, a dual tyrosine kinase inhibitor of the epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2), is clinically active in patients with breast cancer positive for HER2 amplification. The mechanism of this anti-tumor action has remained unclear, however. We have now investigated the effects of lapatinib in HER2 amplification-positive breast cancer cells with or without an activating PIK3CA mutation. Lapatinib induced apoptosis in association with upregulation of the pro-apoptotic protein Bcl-2 interacting mediator of cell death (BIM) through inhibition of the MEK-ERK signaling pathway in breast cancer cells with HER2 amplification. RNA interference (RNAi)-mediated depletion of BIM inhibited lapatinib-induced apoptosis, implicating BIM induction in this process. The pro-apoptotic effect of lapatinib was less pronounced in cells with a PIK3CA mutation than in those without one. Lapatinib failed to inhibit AKT phosphorylation in PIK3CA mutant cells, likely because of hyperactivation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway by the mutation. Depletion of PIK3CA (a catalytic subunit of PI3K) revealed that survivin expression is regulated by the PI3K pathway in these cells, suggesting that insufficient inhibition of PI3K-survivin signaling is responsible for the limited pro-apoptotic effect of lapatinib in HER2 amplification-positive cells with a PIK3CA mutation. Consistent with this notion, depletion of survivin by RNAi or treatment with a PI3K inhibitor markedly increased the level of apoptosis in PIK3CA mutant cells treated with lapatinib. Our results thus suggest that inhibition of both PI3K-survivin and MEK-ERK-BIM pathways is required for effective induction of apoptosis in breast cancer cells with HER2 amplification.

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Other groups have reported similar results in EGFR mutant lung cancers and HER2 gene-amplified breast cell lines with and without activating mutations.
“Other groups have reported similar results in EGFR mutant lung cancers (Ng et al., 2012) and HER2 gene-amplified breast cell lines with and without activating mutations (Tanizaki et al., 2011).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Tanizaki et al., 2011
In cancers with concurrent PIK3CA mutant cells, both the growth inhibitory effect and induction of BIM following treatment with lapatinib were blunted.
“In cancers with concurrent PIK3CA mutant cells, however, both the growth inhibitory effect and induction of BIM following treatment with lapatinib were blunted (Tanizaki et al., 2011).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Tanizaki et al., 2011

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Abstract 2545: Roles of BIM induction and survivin down-regulation in lapatinib-induced apoptosis in breast cancer cells with HER2 amplification
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Authors: Tanizaki, J., Okamoto, I., Fumita, S., Okamoto, W., Nishio, K., & Nakagawa, K.
Affiliations: Kindai University (JP)
Kindai University Hospital (JP)
Corresponding author: Okamoto, I
ORCID: Tanizaki, J
Okamoto, I
Fumita, S
Okamoto, W
Nishio, K
Nakagawa, K
Venue: Oncogene
Publisher: Springer Science and Business Media LLC
Published: 2011-04-18
Volume: 30
Issue: 39
Pages: 4097-4106
ISSN: 0950-9232 (ISSN-L)
1476-5594
DOI: 10.1038/onc.2011.111
OpenAlex: W2139017414
Cited by: 70
References: 40
Citations by year: 2026: 2 · 2024: 4 · 2023: 1 · 2022: 3 · 2021: 4 · 2020: 1 · 2019: 5 · 2018: 2 · 2017: 1 · 2016: 7 · 2015: 7 · 2014: 8 · 2013: 8 · 2012: 16
FWCI: 5.19
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Oncogene (publishedVersion)
PubMed (publishedVersion)
Funders: Japan Society for the Promotion of Science (23650627)
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 › Molecular Biology › Cell death mechanisms and regulation
Keywords: lapatinib, HER2 amplification, breast cancer, apoptosis, building information modeling, survivin, PIK3CA mutation, PI3K signaling, MEK/ERK signaling, Akt phosphorylation, tyrosine kinase inhibitors, PI3K inhibitors
MeSH terms: Survivin, Lapatinib, Antineoplastic Agents, Breast Neoplasms, Female, Humans, Mutation, Phosphorylation, Quinazolines, Signal Transduction, Apoptosis, Erb-b2 Receptor Tyrosine Kinases, Phosphatidylinositol 3-Kinases, MAP Kinase Kinase Kinases, RNA Interference, RNA, Small Interfering, Cell Line, Tumor, Extracellular Signal-Regulated MAP Kinases, Adaptor Proteins, Signal Transducing, Cell Proliferation, Apoptosis Regulatory Proteins, Inhibitor of Apoptosis Proteins, Proto-Oncogene Proteins c-akt, Class I Phosphatidylinositol 3-Kinases

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Roles of BIM induction and survivin downregulation in lapatinib-induced apoptosis in breast cancer cells with HER2 amplification

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