Editors' ChoiceMedicine

Stressing Myc-driven cancer out

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Science Translational Medicine  14 Feb 2018:
Vol. 10, Issue 428, eaar7535
DOI: 10.1126/scitranslmed.aar7535

Abstract

Myc-driven cancers can be targeted with the IRE1α inhibitor.

Myc proteins are amplified or overexpressed in many cancers, and their activation is primarily considered to be oncogenic. However, it is currently difficult to target Myc proteins directly, which represents a major clinical challenge and underscores the need to identify therapeutically targetable vulnerabilities in Myc overexpressing cancers.

Inositol-requiring enzyme 1 (IRE1) represents the most conserved unfolded protein response (UPR) pathway conserved from yeast to mammals. Upon endoplasmic reticulum (ER) stress, IRE1 is activated, resulting in spliced XBP1, which goes on to produce UPR target genes important for ER homeostasis. In a new study, Xie et al. found that c-Myc activated IRE1α-XBP1 and induced ER stress in human Burkitt’s lymphoma (BL). B-I09, an inhibitor specific for IRE1α, decreased XBP1 splicing and caused synthetic lethality in BL cell lines and cell line–derived xenografts both overexpressing c-Myc. Mechanistically, IRE1α inhibition reduced stearoyl-CoA-desaturase 1 (SCD1) expression. SCD1 is a direct transcriptional target of XBP1 essential for c-Myc–driven lymphomas. Similar phenotypes were observed in N-Myc–overexpressing neuroblastoma cells, suggesting that the IRE1α-XBP1-SCD1 signaling axis may be a general regulatory mechanism in many Myc-driven cancers. Compared with the canonical chemotherapeutic drug doxorubicin or a nonspecific Myc inhibitor, B-I09 exhibited higher selectivity in inducing apoptosis in c-Myc–overexpressing cells. When combined with either doxorubicin or another chemotherapy drug, vincristine, IRE1α targeting achieved durable cytotoxicity in the BL cell line. Collectively, this study showed that IRE1α inhibitors may represent a novel therapeutic avenue for treating Myc-driven cancers.

Further investigation should be carried out to understand better how Myc regulates ER stress. In addition, cell line–based work needs to be expanded to patient-derived xenografts and preclinical trials. Therefore, it will be important to identify some reliable molecular markers for Myc activation that can predict response to IRE1α inhibitors. Overall, this exciting study suggests targeting ER stress pathways may be therapeutically beneficial in multiple cancer types.

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