Research ArticleCancer

A small-molecule activator of the unfolded protein response eradicates human breast tumors in mice

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Science Translational Medicine  21 Jul 2021:
Vol. 13, Issue 603, eabf1383
DOI: 10.1126/scitranslmed.abf1383

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Beating back breast cancer

Estrogen receptor–positive breast cancer is the most common type of breast cancer and, in its metastatic form, is currently incurable. In a new study, Boudreau et al. describe a compound, ErSO, that can activate the unfolded protein response, resulting in necrosis of human breast cancer cell lines in vitro. In vivo, this treatment induced complete regression of cell line and patient-derived orthotopic and metastatic breast cancer xenografts in mice. The authors showed that this treatment was well tolerated in mice, rats, and dogs and could provide a new avenue of intervention for this deadly disease.

Abstract

Metastatic estrogen receptor α (ERα)–positive breast cancer is presently incurable. Seeking to target these drug-resistant cancers, we report the discovery of a compound, called ErSO, that activates the anticipatory unfolded protein response (a-UPR) and induces rapid and selective necrosis of ERα-positive breast cancer cell lines in vitro. We then tested ErSO in vivo in several preclinical orthotopic and metastasis mouse models carrying different xenografts of human breast cancer lines or patient-derived breast tumors. In multiple orthotopic models, ErSO treatment given either orally or intraperitoneally for 14 to 21 days induced tumor regression without recurrence. In a cell line tail vein metastasis model, ErSO was also effective at inducing regression of most lung, bone, and liver metastases. ErSO treatment induced almost complete regression of brain metastases in mice carrying intracranial human breast cancer cell line xenografts. Tumors that did not undergo complete regression and regrew remained sensitive to retreatment with ErSO. ErSO was well tolerated in mice, rats, and dogs at doses above those needed for therapeutic responses and had little or no effect on normal ERα-expressing murine tissues. ErSO mediated its anticancer effects through activation of the a-UPR, suggesting that activation of a tumor protective pathway could induce tumor regression.

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