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The pan-ErbB receptor tyrosine kinase inhibitor canertinib promotes apoptosis of malignant melanoma in vitro and displays anti-tumor activity in vivo
Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Department of Plastic Surgery, Hand surgery UHL.
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2011 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 414, no 3, 563-568 p.Article in journal (Refereed) Published
Abstract [en]

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 mu M and by 5 mu M both cell lines were completely growth-arrested within 72 h of treatment. Incubation of exponentially growing RaH3 and RaH5 with 1 mu M canertinib accumulated the cells in the G(1)-phase of the cell cycle within 24 h of treatment without induction of apoptosis as determined by flow cytometry. Immunoblot analysis showed that 1 mu M 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 less than= 5 mu M 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.

Place, publisher, year, edition, pages
Elsevier , 2011. Vol. 414, no 3, 563-568 p.
Keyword [en]
Malignant melanoma; Tyrosine kinase inhibitor; Canertinib; ErbB-receptor; Apoptosis
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-73740DOI: 10.1016/j.bbrc.2011.09.118ISI: 000298519500021OAI: oai:DiVA.org:liu-73740DiVA: diva2:476386
Note

On the day of the defence date the status of this article was Manuscript and the title "The pan-ErbB receptor tyrosine kinase inhibitor Canertinib (CI-1033)promotes cell cycle arrest and apoptosis of human malignantmelanoma in vitro".

Available from: 2012-01-12 Created: 2012-01-12 Last updated: 2017-12-08
In thesis
1. Studies on the effect of ErbB tyrosine kinase inhibitors on malignant melanoma growth and survival in vitro
Open this publication in new window or tab >>Studies on the effect of ErbB tyrosine kinase inhibitors on malignant melanoma growth and survival in vitro
2009 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

Malignant melanoma has one of the fastest increasing incidences among the different types of cancerin the Western world. This raise can partly be ascribed to the change in sun habits that has takenplace during the last decades, since the major external risk factor for melanoma is exposure toultraviolet radiation. Patients with early stages of melanoma can often be cured by surgery, howeverfor patients suffering from metastatic melanoma there are only a few treatment options available.Unfortunately malignant melanoma is often resistant to radio-, bio- and chemotherapy and treatmentwith the currently most frequently used agent, dacarbazine, is characterized by a very low clinicalresponse rate. Therefore, there is an urgent need for new treatment strategies which can increase theoverall survival and cause less severe side effects.

The aim of this thesis was to investigate the anti-tumor effect of two different tyrosine kinaseinhibitors (TKIs), gefitinib and canertinib, on two different human malignant melanoma (RaH3 andRaH5) cell lines. We investigate the effect of these two drugs on cell proliferation and survival andstudied the effect of gefitinib and canertinib on ErbB1-4 receptor phosphorylation, as well as Akt,Erk1/2 and Stat3 activity.

Our results showed that phosphorylation of ErbB1, ErbB2 and ErbB3 decreased followingtreatment with both gefitinib and canertinib and that the subsequent downstream signaling via Akt,Erk1/2 and Stat3 was inhibited after TKI treatment. However, it was noted that the gefitinibinducedinhibition of Akt, and particularly Erk1/2, was transient and only a weak inhibition of Stat3phosphorylation was seen. Gefitinib treatment of the RaH3 and RaH5 cells resulted in anaccumulation of the cells in the G1 phase of the cell cycle without any induction of apoptosis.Canertinib caused a more pronounced inhibition of Akt, Erk1/2, and Stat3 phosphorylation thangefitinib. This might be one explanation to why canertinib induced apoptosis in RaH3 and RaH5cells whereas gefitinib only caused cell cycle arrest. In conclusion, gefitinib and canertinib displaypromising anti-tumor effects on ErbB expressing malignant melanoma and might be used in futurestudies in combination with conventional chemotherapy or other targeted therapies in the treatmentof malignant melanoma.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2009. 56 p.
Series
Linköping Studies in Health Sciences. Thesis, ISSN 1100-6013 ; 100
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-19949 (URN)978-91-7393-610-1 (ISBN)
Presentation
2009-08-28, Karl-Johan salen, Onkologen, Campus US, Linköpings universitet, Linköping, 10:00 (Swedish)
Opponent
Supervisors
Available from: 2009-09-21 Created: 2009-08-19 Last updated: 2012-10-30Bibliographically approved
2. Experimental studies on ErbB targeted therapy in malignant melanoma
Open this publication in new window or tab >>Experimental studies on ErbB targeted therapy in malignant melanoma
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Malignant melanoma has one of the fastest increasing incidences among the different types of cancer in the Western world. This raise can partly be ascribed to the change in sun habits that has taken place during the last decades, since the major external risk factor for melanoma is exposure to ultraviolet radiation. In the case of patients with early stages of melanoma, the prognosis is usually good and the disease may be cured by surgery alone. However, with conventional anti-cancer treatments, patients diagnosed with unresectable or metastatic melanoma have a very low 5-year survival rate ranging from less than 10 percent to about 20 percent, depending on the location and extent of metastatic spread. Despite the development of novel promising targeted drugs, such as the immunomodulating antibody ipilimumab and the B-raf inhibitor vemurafenib, that have been shown to significantly extend patient survival, there is still an urgent need for new and improved treatment strategies which can further increase the survival of patients with advanced malignant melanoma.

The aim of this thesis was to investigate the anti-tumor effect of two different tyrosine kinase inhibitors (TKIs), gefitinib and canertinib, on human malignant melanoma cell lines with wild-type BRAF and NRAS. We investigated the effect of these two drugs on cell proliferation, survival and on the ErbB1-4 receptor phosphorylation, as well as the downstream signaling molecules Akt, Erk1/2 and Stat3. We also established a melanoma cell line resistant to gefitinib treatment and studied the resistance mechanisms developed by the cells.

The aim of this thesis was to investigate the anti-tumor effect of two different tyrosine kinase inhibitors (TKIs), gefitinib and canertinib, on human malignant melanoma cell lines with wild-type BRAF and NRAS. We investigated the effect of these two drugs on cell proliferation, survival and on the ErbB1-4 receptor phosphorylation, as well as the downstream signaling molecules Akt, Erk1/2 and Stat3. We also established a melanoma cell line resistant to gefitinib treatment and studied the resistance mechanisms developed by the cells.

In conclusion, gefitinib and canertinib display promising anti-tumor effects on ErbB-expressing malignant melanoma and might be used in future studies in combination with conventional chemotherapy or other targeted therapies in the treatment of malignant melanoma patients not harboring BRAF or NRAS mutations.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. 104 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1336
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-85665 (URN)978-91-7519-775-3 (ISBN)
Public defence
2012-12-13, Eken, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2012-11-27 Created: 2012-11-27 Last updated: 2013-03-11Bibliographically approved

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Djerf, EmelieTrinks, CeciliaGreen, HenrikAbdiu, AvniHallbeck, Anna-LottaStål, OlleWalz, Thomas

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