Synergistic action of dual IGF1/R and MEK inhibition sensitizes childhood acute lymphoblastic leukaemia (ALL) cells to cytotoxic agents and involves down-regulation of STAT6 and PDAP1

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Abstract

Heterogeneous upregulation of multiple pro-survival pathways underlies resistance to damage-induced apoptosis in acute lymphoblastic leukaemia (ALL) cells despite normal p53 responses. Here we identify the dual combination of IGF1/R and MEK inhibition using AG1024 and U0126 can sensitise apoptosis-resistant ALL cells to ionising radiation (IR)-induced DNA damage irrespective of effect of single pathway inhibition in vitro. This AG1024+U0126 combination also significantly potentiates the ability of the core chemotherapy compounds vincristine, dexamethasone and daunorubicin to kill ALL cells in vitro. Evidence of the synergistic action of AG1024+U0126 in samples with variable basal levels of phosphorylated IGF1/Rβ and ERK1/2 suggested additional targets of this drug combination. Consistent with this, gene expression profiling identified 32 ‘synergy genes’ differentially targeted by IGF1/R+MEK inhibition and among these, STAT6 and PDGF-associated protein 1 (PDAP1) were the most differentially down-regulated cluster. Pearson correlation analyses revealed that STAT6 and PDAP1 display significant expression co-dependency and a common expression pattern linked with other key ‘synergy’ genes supporting their predicted role in an STAT6-ERK-NFKB network. Knockdown studies revealed that loss of STAT6, but not PDAP1, impinges on the cell cycle causing reduced numbers of viable cells. In combination with daunorubicin, STAT6 loss has an additive effect on cell killing whereas PDAP1 loss is synergistic indicating an important role of PDAP1 in the cellular response to this anthracycline. Inhibition of STAT6 or PDAP1 may therefore represent a potential novel therapeutic strategy for resistant ALL by enhancing sensitivity to chemotherapy.

Details

Original languageEnglish
Pages (from-to)52-63.e5
JournalExperimental Hematology
Volume63
Early online date12 Apr 2018
Publication statusPublished - 1 Jul 2018