IRE1α Inhibitors as a Promising Therapeutic Strategy in Blood Malignancies

SIMPLE SUMMARY: Blood malignancies account for 6.9% of all cancer deaths. Inositol-requiring enzyme 1 alpha (IRE1α), a part of the unfolded protein response (UPR), has been shown to be pivotal for cancer cell development and progression, including blood cancers. Furthermore, IRE1α levels are often elevated in blood cancer cells, and they correspond with cell survival, response to treatment, and prognosis. The aim of our study is to summarize the current knowledge on IRE1α in blood cancers and to evaluate the potential utility of IRE1α inhibitors in the treatment of blood malignancies. The introduction of new therapies based on IRE1α inhibition may increase treatment efficacy and reduce the side effects of blood cancer therapy. ABSTRACT: Synthesis, folding, and structural maturation of proteins occur in the endoplasmic reticulum (ER). Accumulation of misfolded or unfolded proteins in the ER lumen contributes to the induction of ER stress and activation of the unfolded protein response (UPR) signaling pathway. Under ER stress, the UPR tries to maintain cellular homeostasis through different pathways, including the inositol-requiring enzyme 1 alpha (IRE1α)-dependent ones. IRE1α is located in an ER membrane, and it is evolutionarily the oldest UPR sensor. Activation of IRE1α via ER stress triggers the formation of the spliced form of XBP1 (XBP1s), which has been linked to a pro-survival effect in cancer cells. The role of IRE1α is critical for blood cancer cells, and it was found that the levels of IRE1α and XBP1s are elevated in various hematological malignancies. This review paper is focused on summarizing the latest knowledge about the role of IRE1α and on the assessment of the potential utility of IRE1α inhibitors in blood cancers.