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Irreversible pan-ERBB inhibitor canertinib elicits anti-leukaemic effects and induces the regression of FLT3-ITD transformed cells in mice
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. 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.
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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. Vol. 155, no 2, 198-208 p.
Keyword [en]
acute myeloid leukaemia, apoptosis, signalling, drugs, murine model, leukaemia therapy
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-72031DOI: 10.1111/j.1365-2141.2011.08819.xISI: 000296063400006OAI: oai:DiVA.org:liu-72031DiVA: diva2:455986
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
In thesis
1. Canertinib-induced leukemia cell death signaling: effects of a pan-ERBB inhibitor
Open this publication in new window or tab >>Canertinib-induced leukemia cell death signaling: effects of a pan-ERBB inhibitor
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:nbn:se:liu:diva-75549 (URN)978-91-7519-983-2 (ISBN)
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
2. The FLT3 Tyrosine Kinase in Leukemia: Deciphering the Downstream Signaling Events and Drug-Escape Mechanisms
Open this publication in new window or tab >>The FLT3 Tyrosine Kinase in Leukemia: Deciphering the Downstream Signaling Events and Drug-Escape Mechanisms
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Acute myeloid leukemia (AML) is a severe disease, which originates in blood-forming cells. Although major advances in understanding the biology of AML, the majority of patients eventually succumb to the disease. The tyrosine kinase receptor FLT3 has become an attractive therapeutic target AML for two major reasons; 1) It is one of the most frequently mutated genes in AML (about 30%). 2) Most of these mutations (FLT3-ITDs) correlate with an increased risk of relapse and poor overall survival. Small targeting inhibitors towards FLT3 have been designed and evaluated in clinical trials. However, the experiences from clinical trials are that drug resistance develops in a substantial number of patients. To overcome these resistance-associated problems it its important to improve the understanding of how FLT3 mutations function and how they respond to targeting drugs. This was addressed in this thesis by elucidating FLT3-ITD cell transformation mechanisms, identifying key downstream target molecules of mutated FLT3 and exploring the effect of various targeting inhibitors. The major finding of my thesis is that FLT3-targeting drugs elicit apoptosis through a FOXO3a-dependent upregulation of proapoptotic BH3-only protein Bim via inactivation of the PI3K/AKT signaling pathway. Furthermore, we have identified an interesting apoptotic mechanism, linked to increased ROS levels caused by expressing hyperactivated AKT in hematopoietic stem cells and bone marrow progenitor cells from FLT3-ITD transgenic mice. These findings are interesting from a therapeutic point of view. We have also shown that canertinib, an inhibitor of the ERBB receptor family, targets mutated FLT3 in vitro and in vivo. The irreversible binding mechanism of canertinib, as well as its multikinase activity, is attractive features. Overall, the results presented herein could provide basis for future directions in treatment of FLT3 mutant positive AML patients. Finally, we studied nine different FLT3-ITD mutations ranging in length from 6-33 amino acids. Data from this study suggest that different FLT3-ITDs may induce distinct degrees of transformation and that they respond differentially to FLT3-targeting drugs. These differences were not associated with size of the duplication but rather the mutational composition. In conclusion, this thesis explores the biologic features of FLT3 mutations and therapeutic targeting opportunities.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2013. 69 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1355
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-88202 (URN)978-91-7519-685-5 (ISBN)
Public defence
2013-02-26, Nils Holgersalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 13:15 (Swedish)
Opponent
Supervisors
Available from: 2013-01-31 Created: 2013-01-31 Last updated: 2017-07-07Bibliographically approved

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Nordigården, AmandaZetterblad, JennyTrinks, CeciliaGreen, HenrikEliasson, PernillaDruid, PiaLotfi, KouroshWalz, ThomasJönsson, Jan-Ingvar

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Nordigården, AmandaZetterblad, JennyTrinks, CeciliaGreen, HenrikEliasson, PernillaDruid, PiaLotfi, KouroshWalz, ThomasJönsson, Jan-Ingvar
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