ArticleCancer biology & therapy2015
PI3K-independent mTOR activation promotes lapatinib resistance and IAP expression that can be effectively reversed by mTOR and Hsp90 inhibition.
Article in Cancer biology & therapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 53 citations in OpenAlex.
- Lapatinib-Resistant HER2+ Breast Cancer Cells Are Associated with Dysregulation of MAPK and p70S6K/PDCD4 Pathways and Calcium Management, Influence of Cryptotanshinone.International journal of molecular sciences · 2025Article
- The Brain-Penetrant Pan-ErbB Inhibitor Poziotinib Effectively Targets HER2+ Breast Cancer Brain Metastases.Cancer research · 2025Article
- Emerging opportunities to treat drug-resistant breast cancer: Discovery of novel small-molecule inhibitors against different targets.Frontiers in pharmacology · 2025Review
- EB1089 Increases the Antiproliferative Response of Lapatinib in Combination with Antiestrogens in HER2-Positive Breast Cancer Cells.International journal of molecular sciences · 2024Article
- Overcoming brain-derived therapeutic resistance in HER2+ breast cancer brain metastasis.bioRxiv : the preprint server for biology · 2024Article
- FilGAP regulates tumor growth in Glioma through the regulation of mTORC1 and mTORC2.Scientific reports · 2023Article
- Targeting mTOR as a Cancer Therapy: Recent Advances in Natural Bioactive Compounds and Immunotherapy.Cancers · 2022Review
- Dual role of deubiquitinating enzyme USP19 regulates mitotic progression and tumorigenesis by stabilizing survivin.Molecular therapy : the journal of the American Society of Gene Therapy · 2022Article
- ERAP2 as a potential biomarker for predicting gemcitabine response in patients with pancreatic cancer.Aging · 2022Article
- Ontogeny and Vulnerabilities of Drug-Tolerant Persisters in HER2+ Breast Cancer.Cancer discovery · 2022Article
- Effects of a combined therapy of bortezomib and ionizing radiation on chondrosarcoma three-dimensional spheroid cultures.Oncology letters · 2021Article
- Review
- Activation of PI3K/AKT/mTOR Pathway Causes Drug Resistance in Breast Cancer.Frontiers in pharmacology · 2021Review
- Adipocyte-conditioned medium induces resistance of breast cancer cells to lapatinib.BMC pharmacology & toxicology · 2020Article
- BMP-2 upregulates the AKT/mTOR pathway in breast cancer with microcalcification and indicates a poor prognosis.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2020Article
- Fibroblast-tumor cell signaling limits HER2 kinase therapy response via activation of MTOR and antiapoptotic pathways.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity.International journal of molecular sciences · 2020Review
- Targeted lapatinib anti-HER2/ErbB2 therapy resistance in breast cancer: opportunities to overcome a difficult problem.Cancer drug resistance (Alhambra, Calif.) · 2020Review
- Targeting the Mevalonate Pathway to Overcome Acquired Anti-HER2 Treatment Resistance in Breast Cancer.Molecular cancer research : MCR · 2019Article
- Oncogenic kinases and perturbations in protein synthesis machinery and energetics in neoplasia.Journal of molecular endocrinology · 2019Review
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Although HER2 targeted therapies have substantially improved outcomes in HER2 overexpressing (HER2+) breast cancer, resistance to these therapies remains a clinical challenge. To better understand the mechanisms of resistance to lapatinib, a HER2 and EGFR dual kinase inhibitor, we treated HER2+ breast cancer cells with lapatinib for an extended period to generate a lapatinib-resistant (LapR) cell line model and examined cancer-promoting signaling activation in LapR cells. We found that LapR cells possess enhanced mTOR activation, which was independent of PI3K and other known mTOR activators. Lapatinib resistance could be reversed by mTOR kinase inhibition. Intriguingly, LapR cells had constitutive cytosolic cytochrome C, indicating that LapR cells suppress lapatinib-induced apoptosis downstream of cytochrome C release from mitochondria into the cytosol rather than by preventing its release into the cytosol. Consistent with this notion, LapR cells possessed increased levels of 2 of the inhibitors of apoptosis (IAPs), survivin and c-IAP-2, which are reported to block caspase activation downstream of cytosolic cytochrome C release. Further, treatment with the mTOR kinase inhibitor AZD8055 or the Hsp90 inhibitor 17-AAG reversed expression of IAPs and overcame lapatinib resistance in LapR cells. Together, these data suggest that suppression of apoptosis downstream of cytosolic cytochrome C release, possibly through increased expression of IAPs or other caspase-suppressing proteins, may promote lapatinib resistance. Further, PI3K is thought to be the main driver of lapatinib resistance, but our findings indicate that PI3K inhibitors may be ineffective in some lapatinib-resistant HER2+ breast cancers with PI3K-independent activation of mTOR kinase, which may instead benefit from mTOR or Hsp90 inhibitors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.