Breast cancer is the most frequent cancer diagnosed in women and 80% of all cases of breast cancer patients present with estrogen receptor (ER)-positive disease. Treatment with antiestrogens most notable tamoxifen and faslodex are effective for a large proportion of ER-positive breast cancer. However, antiestrogen resistance eventually arises in all patients with advanced disease. Thus, antiestrogen resistance represents a major problem in the clinical management of breast cancer patients and there is currently no treatment to overcome resistance to antiestrogens. SCO-101 is an oral drug currently being tested in a Phase II clinical trial enrolling metastatic colorectal cancer patients with drug resistant disease (ClinicalTrials.gov Identifier: NCT04247256). In the current work, we investigated the potential of SCO-101 to act in combination with the antiestrogens tamoxifen or fulvestrant (faslodex) in antiestrogen resistant breast cancer cell lines (MCF-7/LCC-2, MCF-7/LCC-9, T47D/TR1) and - as a negative control - the ER negative MDA-MB-231. Treatment effects were investigated by MTT cell viability assays, siRNA knock-down experiments and western blots. SCO-101 only had minor inhibitory effects on cell viability when administered alone. Interestingly, when combining SCO-101 with tamoxifen or fulvestrant in MCF-7 or T47D antiestrogen resistant breast cancer cells, an additive to synergistic effect on cell viability was observed. In contrast to these results, SCO-101 in combination with antiestrogens had no effects on the triple negative MDA-MB-231 cell line, indicating the ER and or PR (progesterone receptor) is important for the effect of SCO-101 in antiestrogen resistant breast cancer cells. As SCO-101 has been described to targets the volume-regulated anion channel (VRAC), in which LRRC8A is the essential subunit, we investigated whether knockdown of LRRC8A would impact the treatment outcome. No apparent changes in response to SCO-101 and antiestrogens were observed upon the knockdown. Additionally, the protein level of LRRC8A was examined upon treatment with anti-estrogens +/- SCO-101 and the treatment did not alter LRRC8A protein expression. Our findings strongly suggest that SCO-101 interferes with antiestrogen resistance in breast cancer and we have recently received an EURECA Eurostars grant to further investigate the molecular mechanisms of action for SCO-101 in reversing antiestrogen resistance, to investigate drug response in 3D breast cancer models, and to conduct a Phase Ib dose escalation clinical trial with SCO-101 and faslodex in patients with antiestrogen resistant ER positive breast cancer.

Citation Format: Jan Stenvang, Ida CB Madsen, Katrine Hartfelt, Haatisha Jandu, Signe L Nielsen, Palle Christophersen, Nils Brünner. Sco-101 is a novel oral drug that reverses antiestrogen resistance in breast cancer cells [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-43.