Targeting eIF4F translation complex sensitizes B-ALL cells to tyrosine kinase inhibition

Abstract

The mechanistic target of rapamycin (mTOR) is a kinase whose activation is associated with poor prognosis in pre-B cell acute lymphoblastic leukemia (B-ALL). These and other findings have prompted diverse strategies for targeting mTOR signaling in B-ALL and other B-cell malignancies. In cellular models of Philadelphia Chromosome-positive (Ph+) B-ALL, mTOR kinase inhibitors (TOR-KIs) that inhibit both mTOR-complex-1 (mTORC1) and mTOR-complex-2 (mTORC2) enhance the cytotoxicity of tyrosine kinase inhibitors (TKIs) such as dasatinib. However, TOR-KIs have not shown substantial efficacy at tolerated doses in blood cancer clinical trials. Selective inhibition of mTORC1 or downstream effectors provides alternative strategies that may improve selectivity towards leukemia cells. Of particular interest is the eukaryotic initiation factor 4F (eIF4F) complex that mediates cap-dependent translation. Here we use novel chemical and genetic approaches to show that selective targeting of either mTORC1 kinase activity or components of the eIF4F complex sensitizes murine BCR-ABL-dependent pre-B leukemia cells to dasatinib. SBI-756, a small molecule inhibitor of eIF4F assembly, sensitizes human Ph+ and Ph-like B-ALL cells to dasatinib cytotoxicity without affecting survival of T lymphocytes or natural killer cells. These findings support the further evaluation of eIF4F-targeted molecules in combination therapies with TKIs in B-ALL and other blood cancers.

N-MYC regulates cell survival via eIF4G1 in inv(16) acute myeloid leukemia

“…Since c-MYC and N-MYC play a major role in normal hematopoiesis, targeting pathways activated by c-MYC and N-MYC in AML cells will have major therapeutic benefits. The recent development of SBI-756, an eIF4G1 small-molecule inhibitor, has demonstrated promising efficacy in multiple cancer types, including melanoma, B-acute lymphocytic leukemia, and lymphoma ( 68 – 70 ). Future studies using combinations of AI-10-49 with SBI-756 should lead to greater therapeutic responses for inv(16) AML.…”

Ikaros Regulates microRNA Networks in Acute Lymphoblastic Leukemia

“…Two IKZF1 -mutated Ph + B-ALL cell-lines (PDX2 and MXP5) were derived from previously described xenograft-expanded deidentified human B-ALL cells that were initially maintained in vitro on irradiated OP9 stroma cells [ 29 , 45 , 46 , 47 ]. These cells have adapted to in vitro growth without OP9 stroma cell support, and were maintained at 37 °C in humidified incubator with 5% CO 2 in minimum essential medium alpha (MEMα) GlutaMAX (Gibco, Thermo Fisher Scientific, Waltham, MA, USA), supplemented with 20% FBS (Gibco, Thermo Fisher Scientific, Waltham, MA, USA).…”