The pan-ErbB receptor tyrosine kinase inhibitor canertinib promotes apoptosis of malignant melanoma in vitro and displays anti-tumor activity in vivo
Abstract
The ErbB receptor family has been suggested to constitute a therapeutic target for tumor-specific treatment of malignant melanoma. Here we investigate the effect of the pan-ErbB tyrosine kinase inhibitor canertinib on cell growth and survival in human melanoma cells in vitro and in vivo. Canertinib significantly inhibited growth of cultured melanoma cells, RaH3 and RaH5, in a dose-dependent manner as determined by cell counting. Half-maximum growth inhibitory dose (IC(50)) was approximately 0.8 μM and by 5 μM both cell lines were completely growth-arrested within 72 h of treatment. Incubation of exponentially growing RaH3 and RaH5 with 1 μM canertinib accumulated the cells in the G(1)-phase of the cell cycle within 24h of treatment without induction of apoptosis as determined by flow cytometry. Immunoblot analysis showed that 1 μM canertinib inhibited ErbB1-3 receptor phosphorylation with a concomitant decrease of Akt-, Erk1/2- and Stat3 activity in both cell lines. In contrast to the cytostatic effect observed at doses ≤ 5μM canertinib, higher concentrations induced apoptosis as demonstrated by the Annexin V method and Western blot analysis of PARP cleavage. Furthermore, canertinib significantly inhibited growth of RaH3 and RaH5 melanoma xenografts in nude mice. Pharmacological targeting of the ErbB receptors may prove successful in the treatment of patients with metastatic melanoma.
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1 μM canertinib inhibits ErbB1-3 receptor phosphorylation and decreases Akt-, ERK1/2-, and Stat3 activity in RaH3 and RaH5 melanoma cell lines.
“Notably, 1 μM canertinib also inhibits ErbB1-3 receptor phosphorylation and decreases Akt-, ERK1/2-, and Stat3 activity in both cell lines.186–189”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [187]
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Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
Xie, X., Yu, T., Li, X., Zhang, N., Foster, L. J., Peng, C., Huang, W., & He, G. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01589-z · Cited by 396 · see citing works
- Authors
- Djerf Severinsson, E. A., Trinks, C., Gréen, H., Abdiu, A., Hallbeck, A.-L., Stål, O., & Walz, T. M.
- Affiliations
- Linköping University (SE)
- Linköping University Hospital (SE)
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 2011-10
- Volume
- 414
- Issue
- 3
- Pages
- 563-568
- ISSN
- 0006-291X (ISSN-L)
- OpenAlex
- W2009408008
- Cited by
- 24
- References
- 25
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 2 · 2022: 1 · 2021: 2 · 2020: 1 · 2019: 1 · 2018: 2 · 2016: 2 · 2015: 4 · 2014: 4 · 2013: 2 · 2012: 1
- FWCI
- 1.10
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Pfizer
- AstraZeneca
- Topics
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cancer Mechanisms and Therapy
- Keywords
- canertinib, melanoma, apoptosis, G1 cell cycle arrest, Akt signaling, ERK signaling, STAT3 signaling, melanoma xenografts, metastatic melanoma, PARP cleavage
- MeSH terms
- Animals, Antineoplastic Agents, Female, Humans, Melanoma, Mice, Nude, Morpholines, Phosphorylation, Protein-Tyrosine Kinases, Apoptosis, Erb-b2 Receptor Tyrosine Kinases, Mitogen-Activated Protein Kinase 1, Receptor, ErbB-3, Protein Kinase Inhibitors, Mitogen-Activated Protein Kinase 3, Cell Proliferation, STAT3 Transcription Factor, Proto-Oncogene Proteins c-akt, Mice
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