Abstract 2030: Inhibition of IRE1α-XBP1 pathway is a promising therapeutic application in acute myeloid leukemia.

Abstract

Abstract Background: Survival of cancer cells rely on the unfolded protein response (UPR) to resist stress triggered by the accumulation of misfolded proteins within the endoplasmic reticulum (ER). IRE1α-XBP1 pathway, one of the most important branches of the UPR, is activated in different types of cancer. Upon IRE1α activation, the spliced form of XBP1 (XBP1s) is generated to activate the transcription of many pro-survival genes to prevent cellular death and relive cellular stress. Blockade of the IRE1α-XBP1 pathway can thereby be considered as a potential anti-cancer strategy. Results & Clinical relevance: Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Here, we first examined the formation of the XBP1s in leukemia cell lines and AML samples from patients. Interestingly, spliced XBP1 was detectable in 85 % (22 of 26) of leukemia cell lines and 66 % (19 of 29) of AML samples from patients. Compared with normal mononuclear cells from normal individuals, XBP1s was significantly elevated in AML samples from patients (p=0.0043, n=28) as measured by QRT-PCR. 2-hydroxy-1-naphthaldehyde (HNA) is a novel small-molecule inhibitor of the IRE1α-XBP1 pathway, which specifically prevents the splicing of XBP1.HNA blocked both the basal and inducible (tunicamycin treatment) XBP1s in NB-4 and HL60 AML cells, as well as leukemic blasts from AML patients. Furthermore, HNA was able to decrease cellular viability of both AML cell lines (mean IC50=31μM, n=8) and AML samples from patients (mean IC50=35μM, n=18). In contrast, HNA had very low toxicity against normal human marrow mononuclear cells (mean IC50=123 μM, n=4). Importantly, HNA caused a significant inhibition (mean IC50=6 μM, n=6) of clonogenic growth in soft agar of AML cells from patients with different leukemic subtypes. The inhibitory effect trigged by HNA was at least in part mediated through the induction of important regulatory genes for apoptosis, G0/G1 cell cycle arrest and downstream targets of XBP1, namely p53, PARP, p21cip1, p58IPK, CHOP and DNAJB9. Additionally, the combination of HNA with either arsenic trioxide (As2O3) or bortezomib exhibited a synergistic anti-proliferative effect against several human AML cell lines (NB-4 and U-937). Taken together, our results strongly suggest that inhibition of the IRE1α-XBP1 axis is an exciting therapeutic approach for the treatment of AML. Citation Format: Haibo Sun, Behzad Kharabi Masouleh, Sigal Gery, Qi Cao, Tong Yin, Serhan Alkan, Takayuki Ikezoe, Chie Akiba, Ronald Paquette, Wenwen Chien, Carsten Müller-Tidow, Jing Yang, Konstantin Agelopoulos, Muschen Markus, H. Phillip Koeffler. Inhibition of IRE1α-XBP1 pathway is a promising therapeutic application in acute myeloid leukemia. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2030. doi:10.1158/1538-7445.AM2013-2030