Abstract 6236: Systems biology modeling identifies SMARCD3 as a master regulator facilitating everolimus resistance in ER+ breast cancer

Abstract Breast cancer is the most common malignancy in women and estrogen receptor positive (ER+) breast cancers represent nearly 75% of all breast tumors. Everolimus, an mTORC1 inhibitor, in combination with exemestane has been approved for patients with metastatic ER+ breast cancer. However, many patients eventually develop resistance to everolimus and leads to poor survival outcomes. Characterizing everolimus-resistant cells can reveal targetable molecular phenotypes that can eventually lead to new therapeutic targets. In this study, we elucidate systems-level phenotypic distinctions between everolimus sensitive and refractory cells. We generated several isogenic ER+ breast cancer cell lines resistant or sensitive to everolimus. We then leveraged transcriptomic profiles from sensitive and resistant cells before or after everolimus treatment to decipher the underlying mechanisms essential to the resistant state. Using linear mixed effect models, we identified several meta-phenotypes that were distinct between sensitive and resistant cell states. These included growth-factor signaling, cell cycle, metabolism, stemness, and apoptosis meta-phenotypes. Our analyses also identified strong activation of growth-factor receptors including IGF1R/INSR and ESR1 in the resistant cells, which were maintained despite everolimus treatment. Next, we adopted a transcriptional regulatory network reconstruction framework to identify the master regulators responsible for the activation of resistance meta-phenotypes. We identified SMARCD3 as the key master regulator controlling expression of genes across diverse resistance meta-phenotypes, including growth-factor signaling. Further, using transcriptomic profiles from a neoadjuvant trial of 23 post-menopausal ER+ breast cancers treated with everolimus, we found that SMARCD3 expression was elevated in resistant tumors. To confirm the role of SMARCD3 in everolimus resistance, we repressed transcription of the SMARCD3 gene using CRISPR interference to re-sensitize resistant cells to everolimus treatment. In conclusion, we used context-specific cell transcriptomic profiles and integrative systems-biology approaches to elucidate mechanisms of resistance in response to everolimus treatment in ER+ breast cancer. Our findings suggest SMARCD3 upregulation promotes resistance to everolimus treatment and may serve as a novel therapeutic target in ER+ breast cancer. Citation Format: Eric F. Medina, Patrick A. Cosgrove, Eleni Farmaki, Vince K. Grolmusz, Feng Chi, Jason I. Griffiths, Andrea H. Bild, Aritro Nath. Systems biology modeling identifies SMARCD3 as a master regulator facilitating everolimus resistance in ER+ breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6236.