Pharmacological targeting of MYC-regulated IRE1/XBP1 pathway suppresses MYC-driven breast cancer

Abstract

The unfolded protein response (UPR) is a cellular homeostatic mechanism that is activated in many human cancers and plays pivotal roles in tumor progression and therapy resistance. However, the molecular mechanisms for UPR activation and regulation in cancer cells remain elusive. Here, we show that oncogenic MYC regulates the inositol-requiring enzyme 1 (IRE1)/X-box binding protein 1 (XBP1) branch of the UPR in breast cancer via multiple mechanisms. We found that MYC directly controls IRE1 transcription by binding to its promoter and enhancer. Furthermore, MYC forms a transcriptional complex with XBP1, a target of IRE1, and enhances its transcriptional activity. Importantly, we demonstrate that XBP1 is a synthetic lethal partner of MYC. Silencing of XBP1 selectively blocked the growth of MYC-hyperactivated cells. Pharmacological inhibition of IRE1 RNase activity with small molecule inhibitor 8866 selectively restrained the MYC-overexpressing tumor growth in vivo in a cohort of preclinical patient-derived xenograft models and genetically engineered mouse models. Strikingly, 8866 substantially enhanced the efficacy of docetaxel chemotherapy, resulting in rapid regression of MYC-overexpressing tumors. Collectively, these data establish the synthetic lethal interaction of the IRE1/XBP1 pathway with MYC hyperactivation and provide a potential therapy for MYC-driven human breast cancers.

Therapeutic targeting of cellular stress responses in cancer

“…AMPK, HIFα, PGC1α), providing a wide variety of options for pharmaceutical targeting . For example, in the case of MYC‐induced metabolic stress, inhibitors of glutaminase and lactate dehydrogenase have been shown to suppress tumor growth by blocking the flux of the nutrients required for cancer cell proliferation in response to upregulated MYC activity . Similarly, manipulating the response pathways involved in adaptation to MYC‐induced metabolic stress has been also considered as a therapeutic option.…”

“…42 For example, in the case of MYC-induced metabolic stress, inhibitors of glutaminase and lactate dehydrogenase have been shown to suppress tumor growth by blocking the flux of the nutrients required for cancer cell proliferation in response to upregulated MYC activity. 81,82 Similarly, manipulating the response pathways involved in adaptation to MYC-induced metabolic stress has been also considered as a therapeutic option. Targeting the ARK5/AMPK axis was shown to be effective in a hepatocellular carcinoma model, and inhibition of IRE1/XBP1 was promising in triple-negative breast cancer.…”

IRE1α is critical for Kaempferol‐induced neuroblastoma differentiation

“…A). To confirm that XBP1s protein is transcriptionally active, we analyzed its downstream targets such as SEC63, protein disulphide isomerase A 2 ( PDIA2 ) , PDIA3, DnaJ homolog subfamily C 3 ( DNAJC3 ) , endoplasmic reticulum DnaJ 4 and 5 ( ERDJ4 and ERDJ5 ) mRNA level by qRT‐PCR, the regulation of these targets by the transcription factor XBP1s was validated before . These downstream targets of XBP1s transcription factor were not selected randomly; they have certain roles in the events pertaining to cellular differentiation.…”

The multiple roles of the unfolded protein response regulator IRE1α in cancer

“…Similarly, the small molecule IRE1α RNase inhibitor 8866 was shown to enhance the response to docetaxel in Myc‐overexpressing breast tumors. This effect was proposed to be due to XBP1 acting as a synthetic lethal partner for myc . Another IRE1α RNase domain inhibitor, STF‐083010, was used in the human colon cancer cell line HCT116 to manipulate a direct link between p53 and IRE1α, where p53 interacts with the E3 ubiquitin ligase HRD1 that reduces IRE1α levels by proteasomal degradation .…”

“…This effect was proposed to be due to XBP1 acting as a synthetic lethal partner for myc. 62 Another IRE1α…”