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Canertinib-induced leukemia cell death signaling: effects of a pan-ERBB inhibitor
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Acute myelogenous leukemia (AML) is the most common acute leukemia affecting adults, the second most frequent leukemia in children, and remains one of the most difficult to cure. Despite a substantial progress in understanding the pathogenesis of AML, general and rather unspecific cytostatic drugs such as cytarabine and anthracyclins still make up the cornerstones of therapy. Problems with these protocols include toxicity and the occurrence of resistance to the drugs in many patients. In order to extend the treatment options and ultimately improve survival for patients with leukemia it is imperative to increase the therapeutic arsenal with effective targeted therapies, preferentially with different mechanisms of action. AML due to a substantial heterogeneity between patients and within the clones in the same patient, as well as T-cell malignancies, are particularly difficult to treat since it is almost impossible to eradicate all leukemic stem cells using chemotherapy, thus there is a need to find more specific and effective treatments. Canertinib is a novel tyrosine kinase inhibitor developed for the treatment of certain solid cancers and has been designed to specifically inhibit all member of the ERBB-receptor family (ERBB1, ERBB2, ERBB3 and ERBB4). However, there are indications that canertinib has a broader specificity and it has not been tested on patients with leukemia.

The aim of this thesis was to investigate the anti-proliferative and pro-apoptotic effects and mechanisms of canertinib in human leukemia cells, and more specifically to clarify the cell death pathway and potential targets for the drug in these cells.

Canertinib treatment of leukemia cell lines resulted in an ERBB-independent induction of the intrinsic apoptotic pathway and activation of caspase-10, -9, and -8 as a consequence of Akt and Erk inhibition. In the human T-cell leukemia cell line Jurkat, the effects were associated to dephosphorylation of the lymphocyte-specific proteins, Lck and Zap-70. However, as full-length ERBB receptors were absent in leukemic cell lines other possible targets for canertinib were investigated. The FLT3 receptor, frequently mutated in AML, was discovered as a target since canertinib inhibited FLT3 autophosphorylation and kinase activity as well as downstream targets. The search for other possible proteins that might account for the effect exerted by canertinib, lead to the discovery of a truncated form of ERBB2 in human leukemic cells.

In conclusion, canertinib display promising anti-tumor effects on malignant hematopoietic cells and might be used in future studies in combination with conventional chemotherapy or other targeted therapies in the treatment of leukemia.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. , 76 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1289
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-75549ISBN: 978-91-7519-983-2 (print)OAI: oai:DiVA.org:liu-75549DiVA: diva2:508130
Public defence
2012-03-30, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2012-03-07 Created: 2012-03-07 Last updated: 2012-10-30Bibliographically approved
List of papers
1. The pan-ErbB receptor tyrosine kinase inhibitor canertinib induces ErbB-independent apoptosis in human leukemia (HL-60 and U-937) cells
Open this publication in new window or tab >>The pan-ErbB receptor tyrosine kinase inhibitor canertinib induces ErbB-independent apoptosis in human leukemia (HL-60 and U-937) cells
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2010 (English)In: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, ISSN 0006-291X, Vol. 393, no 1, 6-10 p.Article in journal (Refereed) Published
Abstract [en]

Epidermal growth factor (EGF) receptor tyrosine kinase inhibitors have recently been shown to display anti-neoplastic effects in human malignant myeloid cells. Our study was initiated in order to determine the effect of the pan-ErbB receptor tyrosine kinase inhibitor, canertinib (CI-1033), on growth and survival of human leukemia (HL-60 and U-937) cells. We show that treatment of HL-60 and U-937 cells with canertinib significantly inhibits growth of both cell lines in a dose-dependent manner; half maximal effective dose (IC50) in HL-60 and U-937 cells was approximately 2.5 mu M and 1.0 mu M, respectively. Treatment with 2 mu M canertinib promoted a G(1) cell cycle arrest, whereas doses of 5 mu M or more induced apoptosis as determined by the Annexin V method and cleavage of poly-(ADP-ribose) polymerase (PARP). HL-60 and U-937 cells lacked EGF-receptor transcript but expressed ErbB2-4 mRNA as determined by RTPCR. However, none of the corresponding ErbB-receptor proteins could be detected by Western blot analysis. We conclude that canertinib induces apoptosis in HL-60 and U-937 cells devoid of functional ErbB1-4 receptors. Our results suggest that canertinib could be of potential clinical interest in the treatment of acute myeloid leukemia.

Keyword
Leukemia, Tyrosine kinase inhibitor, CI-1033, ErbB-receptor, Growth inhibition, Apoptosis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-54619 (URN)10.1016/j.bbrc.2010.01.055 (DOI)000275371300002 ()
Available from: 2010-03-26 Created: 2010-03-26 Last updated: 2012-10-30
2. The pan-ErbB tyrosine kinase inhibitor canertinib induces caspase-mediated cell death in human T-cell leukemia (Jurkat) cells
Open this publication in new window or tab >>The pan-ErbB tyrosine kinase inhibitor canertinib induces caspase-mediated cell death in human T-cell leukemia (Jurkat) cells
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2011 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 410, no 3, 422-427 p.Article in journal (Refereed) Published
Abstract [en]

Canertinib is a novel ErbB-receptor inhibitor currently in clinical development for the treatment of solid tumors overexpressing ErbB-receptors. We have recently demonstrated that canertinib displays anti-proliferative and pro-apoptotic effects in human myeloid leukemia cells devoid of ErbB-receptors. The mechanism mediating these effects are however unknown. In this study, we show that canertinib is able to act as a multi-kinase inhibitor by inhibition of several intracellular kinases involved in T-cell signaling such as Akt, Erk1/2 and Zap-70, and reduced Lck protein expression in the human T-cell leukemia cell line Jurkat. Treatment with canertinib at a concentration of 2 mu M caused accumulation of Jurkat cells in the G(1) cell cycle phase and increased doses induced apoptosis in a time-dependent manner. Apoptotic signs of treated cells were detected by Annexin V staining and cleavage of PARP, caspase-3, -8, -9, -10 and Bid. A subset of the pro-apoptotic signals mediated by canertinib could be significantly reduced by specific caspase inhibitors. Taken together, these results demonstrate the dual ability of canertinib to downregulate important signaling pathways and to activate caspase-mediated intrinsic apoptosis pathway in human T-cell leukemia cells.

Place, publisher, year, edition, pages
Elsevier Science B.V., Amsterdam, 2011
Keyword
T-cell leukemia; Canertinib; ErbB-receptor; Apoptosis; Caspase; Intracellular signaling
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-69797 (URN)10.1016/j.bbrc.2011.05.148 (DOI)000292797700009 ()
Available from: 2011-08-10 Created: 2011-08-08 Last updated: 2017-12-08
3. Irreversible pan-ERBB inhibitor canertinib elicits anti-leukaemic effects and induces the regression of FLT3-ITD transformed cells in mice
Open this publication in new window or tab >>Irreversible pan-ERBB inhibitor canertinib elicits anti-leukaemic effects and induces the regression of FLT3-ITD transformed cells in mice
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2011 (English)In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 155, no 2, 198-208 p.Article in journal (Refereed) Published
Abstract [en]

Recent findings have indicated that tyrosine kinase inhibitors (TKIs) targeting the ERBB receptor family display anti-leukaemic effects, despite the lack of receptor expression on human leukaemic cells. The occurrence of activating mutations in the gene encoding FMS-like tyrosine kinase 3 (FLT3) in patients with acute myeloid leukaemia (AML) has rendered inhibition of this receptor a promising therapeutic target. Due to possibility of cross-reactivity, we investigated the effect of the irreversible pan-ERBB inhibitor canertinib (CI-1033) on leukaemic cells expressing FLT3. The drug had anti-proliferative and apoptotic effects on primary AML cells and human leukaemic cell lines expressing mutated FLT3. In several AML patient samples, a blast cell population expressing FLT3-internal tandem duplication (ITD) was eradicated by canertinib. Canertinib inhibited receptor autophosphorylation and kinase activity of both mutated and FLT3 ligand stimulated wildtype FLT3, leading to inhibition of the PI3-kinase and MAP kinase pathways. Apoptotic induction was dependent on pro-apoptotic BH3-only protein BCL2L11/BIM because siRNA silencing attenuated apoptosis. Moreover, the drug induced regression of cells expressing FLT3-ITD in a murine in vivo-transplantation model at previously described tolerated doses. These results indicate that canertinib, as an irreversible TKI, could constitute a novel treatment regimen in patients with mutated or overexpressed FLT3.

Place, publisher, year, edition, pages
Blackwell Publishing, 2011
Keyword
acute myeloid leukaemia, apoptosis, signalling, drugs, murine model, leukaemia therapy
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-72031 (URN)10.1111/j.1365-2141.2011.08819.x (DOI)000296063400006 ()
Note
Funding Agencies|Swedish Cancer Foundation||Swedish Childrens Cancer Foundation||Swedish Research Council||County Council of Ostergotland||Cancer Foundation of Ostergotland||Ollie and Elof Ericssons Foundation||Available from: 2011-11-11 Created: 2011-11-11 Last updated: 2017-12-08
4. Human leukemic cell lines express a truncated intracellular 160 kDa ERBB2 receptor
Open this publication in new window or tab >>Human leukemic cell lines express a truncated intracellular 160 kDa ERBB2 receptor
(English)Manuscript (preprint) (Other academic)
Abstract [en]

It has recently been demonstrated that ERBB specific tyrosine kinase inhibitors display antineoplastic activity in human leukemic cell devoid of functional ERBB receptors. The present study was undertaken in order to identify any putative target for these drugs. Flow cytometry experiments demonstrate the presence of an immunoreactive ERBB2 protein of intracellular localization and Western blot analysis visualized an ERBB2 protein of approximately 160 kDa. Exposing leukemia cells to tunicamycin did not alter the size of the truncated ERBB2 protein. The ERBB2 gene was alternative spliced with an absence of exon 5 containing the start codon for the full-length protein. In conclusion we demonstrate a nonglycosylated 160 kDa ERBB2-receptor protein with an alternative in-frame start codon in human leukemia cell lines.

Keyword
Leukemia, ERBB2-receptor, variant, glycosylation, exon
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-75548 (URN)
Available from: 2012-03-07 Created: 2012-03-07 Last updated: 2012-03-07Bibliographically approved

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