System analysis links SMARCD3 regulons to growth signaling and MEK inhibitor response in everolimus-resistant ER+ breast cancer cells

Estrogen receptor-positive breast cancer (ER+BC) accounts for ∼70% of all breast tumors, and 20%-40% of patients develop metastases. Everolimus is an mammalian target of rapamycin (mTOR) inhibitor used in combination with exemestane for metastatic ER+BC. However, resistance remains common and leads to poor survival outcomes. To uncover resistance mechanisms, we analyze transcriptomic profiles from everolimus-sensitive and -resistant ER+BC cell lines. Our study uncovers persistent activation of a growth-factor signaling meta-phenotype in resistant cells involving IGF1R, ESR1, and mitogen-activated protein kinase (MAPK) pathways. We identify SMARCD3 regulons linked to this meta-phenotype. Additionally, we find SMARCD3 regulon activity elevated in everolimus-refractory patient tumors. Importantly, we show that SMARCD3 regulon activation was correlated with sensitivity to several known MEK1/2 inhibitors, including trametinib. Combining trametinib with everolimus treatment significantly reduces resistant cell growth. Our results demonstrate that everolimus-resistant ER+BC cells evade therapy via alternate growth-factor signaling linked to activation of SMARCD3 regulons, which can be therapeutically targeted using MEK1/2 inhibitors.