Irreversible pan-ERBB inhibitor canertinib elicits anti-leukaemic effects and induces the regression of FLT3-ITD transformed cells in mice.
(2011) In British Journal of Haematology 155. p.198-208- Abstract
- 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... (More)
- 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. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/2150951
- author
- Nordigården, Amanda ; Zetterblad, Jenny ; Trinks, Cecilia ; Green, Henrik ; Eliasson, Pernilla ; Druid, Pia ; Lotfi, Kourosh ; Rönnstrand, Lars LU ; Walz, Thomas M and Jönsson, Jan-Ingvar
- organization
- publishing date
- 2011
- type
- Contribution to journal
- publication status
- published
- subject
- in
- British Journal of Haematology
- volume
- 155
- pages
- 198 - 208
- publisher
- Wiley-Blackwell
- external identifiers
-
- wos:000296063400006
- pmid:21848891
- scopus:80053576720
- pmid:21848891
- ISSN
- 0007-1048
- DOI
- 10.1111/j.1365-2141.2011.08819.x
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Experimental Clinical Chemistry (013016010)
- id
- 95274325-5a1c-4f57-bb8a-b2b3d449c412 (old id 2150951)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/21848891?dopt=Abstract
- date added to LUP
- 2016-04-04 08:45:10
- date last changed
- 2022-06-11 07:42:53
@article{95274325-5a1c-4f57-bb8a-b2b3d449c412, abstract = {{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.}}, author = {{Nordigården, Amanda and Zetterblad, Jenny and Trinks, Cecilia and Green, Henrik and Eliasson, Pernilla and Druid, Pia and Lotfi, Kourosh and Rönnstrand, Lars and Walz, Thomas M and Jönsson, Jan-Ingvar}}, issn = {{0007-1048}}, language = {{eng}}, pages = {{198--208}}, publisher = {{Wiley-Blackwell}}, series = {{British Journal of Haematology}}, title = {{Irreversible pan-ERBB inhibitor canertinib elicits anti-leukaemic effects and induces the regression of FLT3-ITD transformed cells in mice.}}, url = {{http://dx.doi.org/10.1111/j.1365-2141.2011.08819.x}}, doi = {{10.1111/j.1365-2141.2011.08819.x}}, volume = {{155}}, year = {{2011}}, }