- Meyer, Lauren K;
- Delgado‐Martin, Cristina;
- Sharp, Phillip P;
- Huang, Benjamin J;
- McMinn, Dustin;
- Vincent, Tiffaney L;
- Ryan, Theresa;
- Horton, Terzah M;
- Wood, Brent L;
- Teachey, David T;
- Taunton, Jack;
- Kirk, Christopher J;
- Hermiston, Michelle L
Glucocorticoid (GC) resistance is a poor prognostic factor in T-cell acute lymphoblastic leukaemia (T-ALL). Interleukin-7 (IL-7) mediates GC resistance via GC-induced upregulation of IL-7 receptor (IL-7R) expression, leading to increased pro-survival signalling. IL-7R reaches the cell surface via the secretory pathway, so we hypothesized that inhibiting the translocation of IL-7R into the secretory pathway would overcome GC resistance. Sec61 is an endoplasmic reticulum (ER) channel that is required for insertion of polypeptides into the ER. Here, we demonstrate that KZR-445, a novel inhibitor of Sec61, potently attenuates the dexamethasone (DEX)-induced increase in cell surface IL-7R and overcomes IL-7-induced DEX resistance.