Figure 3: Therapeutic Targeting of the UPR in Leukemia.

Given the dual ability of the UPR to either promote cell survival or induce death, two differing strategies could be used to target the ER stress response in leukemia. The first (left) includes inhibiting the UPR cytoprotective arms associated with the IRE1/XBP1or PERK axes. The goal of the second approach (right) would be to exacerbate ER stress to promote pro-apoptotic signaling. The rationale is that cancer cells display higher basal ER stress than do normal cells and will thus display increased susceptibility to ER stress-inducing drugs. Among these types of drugs tested preclinically against leukemia are chaperone inhibitors, as indicated, which prevent sequestration of un-/mis-folded proteins in the ER, thereby increasing ER stress. Moreover, ERAD inhibitors, which prevent retro-translocation of un-/misfolded proteins from the ER to the cytosol for proteasomal degradation, may interfere with the ER’s ability to resolve stress. Finally, treatment with drugs which prevents protein glycosylation and thus protein export from the ER (right), promotes protein retention in the ER, thereby inducing stress. FLT3-ITD positive AML may be especially vulnerable to such treatment, as in addition to inducing ER stress, these drugs prevent FLT3-ITD glycosylation and export from the ER, thereby decreasing FLT3-ITD oncogenic signaling [81]. Candidate UPR inhibitors are listed in Table 1.