Irreversible pan-ERBB inhibitor canertinib elicits anti-leukaemic effects and induces the regression of FLT3-ITD transformed cells in mice
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
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.
acute myeloid leukaemia, apoptosis, signalling, drugs, murine model, leukaemia therapy
National CategoryMedical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-72031DOI: 10.1111/j.1365-2141.2011.08819.xISI: 000296063400006OAI: oai:DiVA.org:liu-72031DiVA: diva2:455986
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||2011-11-112011-11-112013-01-31