Trastuzumab-resistant cells rely on a HER2-PI3K-FoxO-survivin axis and are sensitive to PI3K inhibitors
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Abstract
The antibody trastuzumab is approved for treatment of patients with HER2 (ERBB2)-overexpressing breast cancer. A significant fraction of these tumors are either intrinsically resistant or acquire resistance rendering the drug ineffective. The development of resistance has been attributed to failure of the antibody to inhibit phosphoinositide 3-kinase (PI3K), which is activated by the HER2 network. Herein, we examined the effects of PI3K blockade in trastuzumab-resistant breast cancer cell lines. Treatment with the pan-PI3K inhibitor XL147 and trastuzumab reduced proliferation and pAKT levels, triggering apoptosis of trastuzumab-resistant cells. Compared with XL147 alone, the combination exhibited a superior antitumor effect against trastuzumab-resistant tumor xenografts. Furthermore, treatment with XL147 and trastuzumab reduced the cancer stem-cell (CSC) fraction within trastuzumab-resistant cells both in vitro and in vivo. These effects were associated with FoxO-mediated inhibition of transcription of the antiapoptosis gene survivin (BIRC5) and the CSC-associated cytokine interleukin-8. RNA interference-mediated or pharmacologic inhibition of survivin restored sensitivity to trastuzumab in resistant cells. In a cohort of patients with HER2-overexpressing breast cancer treated with trastuzumab, higher pretreatment tumor levels of survivin RNA correlated with poor response to therapy. Together, our results suggest that survivin blockade is required for therapeutic responses to trastuzumab and that by combining trastuzumab and PI3K inhibitors, CSCs can be reduced within HER2(+) tumors, potentially preventing acquired resistance to anti-HER2 therapy.
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Elevated levels of survivin and MCL-1 have been found in trastuzumab-resistant cells.
“Accordingly, elevated levels of survivin and MCL-1 have been found in trastuzumab-resistant cells (Chakrabarty et al., 2013).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Chakrabarty et al., 2013
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ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics
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- Authors
- Chakrabarty, A., Bhola, N. E., Sutton, C., Ghosh, R., Kuba, M. G., Dave, B., Chang, J. C., & Arteaga, C. L.
- Affiliations
- Houston Methodist (US)
- Corresponding author
- Arteaga, Carlos L.
- ORCID
- Venue
- Cancer Research
- Published
- 2013-01-31
- Volume
- 73
- Issue
- 3
- Pages
- 1190-1200
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3563941
- OpenAlex
- W2109762821
- Cited by
- 130
- References
- 49
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 15 · 2023: 8 · 2022: 2 · 2021: 4 · 2020: 5 · 2019: 6 · 2018: 6 · 2017: 13 · 2016: 10 · 2015: 20 · 2014: 22 · 2013: 11
- FWCI
- 8.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P50 CA98131, R01 CA80195, P30 CA 68485, R01CA080195, P50CA098131, P30CA068485)
- 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
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Gastric Cancer Management and Outcomes
- Keywords
- trastuzumab resistance, HER2-positive breast cancer, PI3K inhibitors, survivin, FOXO, cancer stem cells, interleukin-8, apoptosis, Akt phosphorylation, combination therapy, acquired drug resistance, predictive biomarkers
- MeSH terms
- Trastuzumab, Forkhead Box Protein O1, Forkhead Box Protein O3, Survivin, Phosphoinositide-3 Kinase Inhibitors, Animals, Antineoplastic Agents, Female, Humans, Neoplastic Stem Cells, Erb-b2 Receptor Tyrosine Kinases, Drug Resistance, Neoplasm, Phosphatidylinositol 3-Kinases, Inhibitor of Apoptosis Proteins, Mice, Forkhead Transcription Factors, Antibodies, Monoclonal, Humanized
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