Irreversible pan‐ERBB inhibitor canertinib elicits anti‐leukaemic effects and induces the regression of FLT3‐ITD transformed cells in mice

Abstract

Summary 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.

Targeted ex vivo reduction of CD64‐positive monocytes in chronic myelomonocytic leukemia and acute myelomonocytic leukemia using human granzyme B‐based cytolytic fusion proteins

“…Dose‐depending viability assays showed typical sigmoidal characteristics. The granzyme B constructs were less potent towards primary cells than cell lines, as previously reported for primary AML cells . This reflects the mixed lineage of CMML cells, with only part of the cell population derived from the CD64 + monocytic lineage and others derived from CD64 – progenitors.…”

“…The granzyme B constructs were less potent towards primary cells than cell lines, as previously reported for primary AML cells. 41,42,45 This reflects the mixed lineage of CMML cells, with only part of the cell population derived from the CD64 1 monocytic lineage and others derived from CD64 -progenitors. The CD64-dependent enrichment of target cells was not feasible because the receptor would be blocked.…”

miR-125a regulates cell cycle, proliferation, and apoptosis by targeting the ErbB pathway in acute myeloid leukemia

“…Martin-Subero et al discovered that ErbB2 was amplified within a Myelodysplatic Syndrome (MDS) patient who developed AML(33). Further studies by Nordigården et al demonstrate that canertinib, a pan-ERBB inhibitor is effective in both primary samples and within a murine model for treatment of FMS-like tyrosine kinase 3 (FLT3) in patients with acute myeloid leukaemia (AML) (34). …”

miRNAs in acute myeloid leukemia

“…Inhibition of the ErbB pathway provides another potential new therapeutic target for leukemia [86, 87]. In AML NB4 cells ectopically expressing miR-125a ErbB pathway was significantly activated.…”