Silencing c-Myc translation as a therapeutic strategy through targeting PI3K delta and CK1 epsilon in hematological malignancies

摘要

Phosphoinositide 3-kinase (PI3K) and the proteasome pathway are both involved in activating themechanistic target of rapamycin (mTOR). BecausemTORsignaling is required for initiation of messenger RNA translation, we hypothesized that cotargeting the PI3K and proteasome pathways might synergistically inhibit translation of c-Myc. We found that a novel PI3K delta isoform inhibitor TGR-1202, but not the approved PI3K delta inhibitor idelalisib, was highly synergistic with the proteasome inhibitor carfilzomib in lymphoma, leukemia, and myelomacell linesandprimarylymphomaandleukemiacells. TGR-1202 and carfilzomib (TC) synergistically inhibited phosphorylation of the eukaryotic translation initiation factor 4E (eIF4E)-bindingprotein 1 (4E-BP1), leading to suppression of c-Myc translation and silencing of c-Myc-dependent transcription. The synergistic cytotoxicity of TC was rescued by overexpression of eIF4E or c-Myc. TGR-1202, but not other PI3K delta inhibitors, inhibited casein kinase-1 epsilon (CK1 epsilon). Targeting CK1 epsilon using a selective chemical inhibitor or short hairpin RNA complements the effects of idelalisib, as a single agent or in combination with carfilzomib, in repressing phosphorylation of 4E-BP1 and the protein level of c-Myc. These results suggest that TGR-1202 is a dual PI3K delta/CK1 epsilon inhibitor, whichmay in part explain the clinical activity of TGR-1202 in aggressive lymphoma not found with idelalisib. Targeting CK1 epsilon should become an integral part of therapeutic strategies targeting translation of oncogenes such as c-Myc.