Abstract
Endocrine resistance is frequently encountered in the clinic through a variety of mechanisms such as NF1 loss that induce alternative survival pathways and suppress estrogen responsiveness. While targeting the induced pathways such as the RAS-MAPK pathway can have antitumor effects, it can also incur toxicities. To identify novel and potentially more specific therapeutic vulnerabilities in this context, we performed CRISPR/Cas9 screens in wildtype and NF1 knockout isogenic ER+ models and identified NR2F2, an orphan nuclear receptor, to be essential specifically in NF1 loss cells. Our in vitro and in vivo results revealed that NR2F2 is a critical regulator of the estrogen signaling pathway, largely playing a repressive role. We found that NF1 loss could upregulate NR2F2 expression level in ER+ breast cancer cells through the activation of the MAPK pathway. NR2F2 overexpression by itself conferred endocrine resistance, while genetic knockout and pharmacologic inhibition of NR2F2 sensitized ER+ breast cancer cells to endocrine therapies and attenuated resistance across multiple endocrine refractory tumor models including those driven by NF1 loss, ARID1A loss, and PTEN loss. These results reveal upregulation of NR2F2 to be a recurrent mechanism whereby hormone responsiveness is suppressed. At a mechanistic level, investigation into chromatin accessibility and transcription revealed that altered NR2F2 expression modulates genome-wide chromatin accessibility including ER-regulated loci and modulates ER transcriptional activity through its direct interactions with ER and its transcriptional coregulators. Collectively, our data unveil a critical mechanism whereby endocrine resistance occurs through the repression of estrogen responsiveness and highlight a new therapeutic approach to restore endocrine response through pharmacologic inhibition of NR2F2.
Citation Format: Yanyan Cai, Peihua Zhao, Fan Wu, Huiyong Zhao, Hong Shao, Antonio Marra, Payal Patel, Elizabeth O’Connell, Emma Fink, Matthew M Miele, Zhuoning Li, Elisa De Stanchina, Emiliano Cocco, Pedram Razavi, Eneda Toska, Sean W Fanning, Guotai Xu, Anna A Sablina, Sarat Chandarlapaty. Targeting NR2F2 overcomes multiple forms of endocrine resistance [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-03-17.