Small molecule-mediated ERO1A inhibition in restraining aggressive breast cancer
Cancer cells adapt to harsh environmental conditions by inducing the Unfolded Protein Response (UPR), of which ERO1A is one of the mediators. ERO1A aids protein folding by acting as a protein disulfide oxidase, and under cancer-related hypoxia conditions, it favors the folding of angiogenic VEGFA, leading tumor cells to thrive and spread. The upregulation of ERO1A in cancer and the dispensability of ERO1A activity in healthy cells render ERO1 a perfect target for cancer therapy. Here, we report the upregulation of ERO1 in aggressive triple-negative breast cancer (TNBC) patients. Thus, we designed new ERO1A inhibitors in a campaign of lead compound optimization on the prototype EN460 to be tested in TNBC treatment. Cell-based screenings showed that I2 and I3, two novel EN460 analogs, inhibited ERO1A efficiently, thus blunting VEGFA secretion. Accordingly, in vitro assays to measure ERO1A engagement confirmed that I2 and I3 bind ERO1A. EN460, I2 and I3 triggered breast cancer cytotoxicity while specifically inhibiting ERO1A in a dose-dependent manner. I2 more efficiently impaired cancer-relevant features such as VEGFA secretion and the related cell migration. Furthermore, I2 impinged on the tumor microenvironment and viability of xenografts and syngeneic TNBC. Thus, ERO1A pharmacological inhibition promises to lead to an effective anti-cancer therapy for the yet incurable TNBC.