A model of acquired autoresistance to a potent ErbB2 tyrosine kinase inhibitor and a therapeutic strategy to prevent its onset in breast cancer
Open accessAbstract
The development of acquired resistance to ErbB2 tyrosine kinase inhibitors limits the clinical efficacy of this class of cancer therapeutics. Little is known about the mechanism(s) of acquired resistance to these agents. Here we establish a model of acquired resistance to N-{3-chloro-4-[(3-fluorobenzyl) oxy]phenyl}-6-[5-({[2 (methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine (lapatinib), an inhibitor of ErbB2 and ErbB1 tyrosine kinases by chronically exposing lapatinib-sensitive ErbB2-overexpressing breast cancer cells to lapatinib, simulating the clinic where lapatinib is administered on a daily chronic basis. Analysis of baseline gene expression in acquired lapatinib-resistant and parental cells indicates estrogen receptor (ER) signaling involvement in the development of resistance. Using gene interference, we confirm that acquired resistance to lapatinib is mediated by a switch in cell survival dependence and regulation of a key antiapoptotic mediator from ErbB2 alone to codependence upon ER and ErbB2 rather than loss of ErbB2 expression or insensitivity of ErbB2 signaling to lapatinib. Increased ER signaling in response to lapatinib is enhanced by the activation of factors facilitating the transcriptional activity of ER, notably FOXO3a and caveolin-1. Importantly, we confirm that lapatinib induces ER signaling in tumor biopsies from patients with ErbB2-overexpressing breast cancers receiving lapatinib therapy. These findings provided the rationale for preventing the development of acquired resistance by simultaneously inhibiting both ER and ErbB2 signaling pathways. Establishing clinically relevant models of acquired resistance to ErbB2 kinase inhibitors will enhance therapeutic strategies to improve clinical outcomes for patients with ErbB2-overexpressing breast cancers.
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High survivin levels allow for escape from lapatinib.
“In turn, high survivin levels allow for escape from lapatinib.”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Xia et al., 2006
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ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics
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- Authors
- Xia, W., Bacus, S., Hegde, P., Husain, I., Strum, J., Liu, L., Paulazzo, G., Lyass, L., Trusk, P., Hill, J., Harris, J., & Spector, N. L.
- Affiliations
- GlaxoSmithKline (United States) (US)
- Targeted Molecular Diagnostics, Westmont, IL 60559
- Departments of *Oncology Biology and
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2006-05-16
- Volume
- 103
- Issue
- 20
- Pages
- 7795-7800
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1472524
- OpenAlex
- W2086224272
- Cited by
- 374
- References
- 43
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 11 · 2023: 10 · 2022: 4 · 2021: 10 · 2020: 9 · 2019: 8 · 2018: 17 · 2017: 18 · 2016: 19 · 2015: 25 · 2014: 20 · 2013: 31 · 2012: 30
- FWCI
- 14.21
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- acquired drug resistance, lapatinib, HER2-positive breast cancer, estrogen receptor signaling, FOXO3, caveolin-1, anti-apoptotic signaling, combination therapy, resistance prevention
- MeSH terms
- Forkhead Box Protein O3, Lapatinib, Antineoplastic Agents, Breast Neoplasms, Cell Survival, Female, Humans, Quinazolines, Receptors, Estrogen, Signal Transduction, Erb-b2 Receptor Tyrosine Kinases, Drug Resistance, Neoplasm, Estrogen Receptor Modulators, RNA, Small Interfering, Cell Line, Tumor, Protein Kinase Inhibitors, Forkhead Transcription Factors
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