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A small-molecule activator of the unfolded protein response eradicates human breast tumors in mice
Matthew W Boudreau1,2, Darjan Duraki3, Lawrence Wang3
1Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
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.
Insights
A new compound, ErSO, effectively targets metastatic estrogen receptor-positive breast cancer by activating the anticipatory unfolded protein response (a-UPR), leading to tumor regression in preclinical models without recurrence or significant side effects.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Metastatic estrogen receptor α (ERα)-positive breast cancer remains incurable.
- Drug resistance is a significant challenge in treating these cancers.
Purpose of the Study:
- To discover and evaluate a novel compound, ErSO, for its efficacy against metastatic ERα-positive breast cancer.
- To investigate the mechanism of action of ErSO, specifically its effect on the anticipatory unfolded protein response (a-UPR).
Main Methods:
- In vitro studies on ERα-positive breast cancer cell lines.
- In vivo preclinical testing in orthotopic and metastasis mouse models with human breast cancer xenografts.
- Evaluation of ErSO's tolerability and effects on normal tissues in mice, rats, and dogs.
Main Results:
- ErSO induced rapid and selective necrosis of ERα-positive breast cancer cells in vitro.
- ErSO treatment led to significant tumor regression without recurrence in orthotopic mouse models.
- ErSO effectively reduced lung, bone, liver, and brain metastases in various preclinical models.
- Regrown tumors remained sensitive to retreatment with ErSO.
- ErSO was well tolerated and showed minimal impact on normal ERα-expressing tissues.
Conclusions:
- ErSO demonstrates potent anticancer activity against metastatic ERα-positive breast cancer.
- Activation of the a-UPR by ErSO is the key mechanism for its therapeutic effects.
- ErSO represents a promising therapeutic candidate for treating drug-resistant, metastatic ERα-positive breast cancer.
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