Abstract 835: Estrogen receptor expression and ER dependent breast tumor growth are dependent on translation initiation factor EIF4A

• Published in: Cancer research (Chicago, Ill.) Ill.), 2022-06, Vol.82 (12_Supplement), p.835-835
• Main Authors: Boyer, Jacob A., Dorso, Madeline A., Amor, Corina, Reiter, Jason, Xu, Jianing, de Stanchina, Elisa, Wendel, Hans-Guido, Chandarlapaty, Sarat, Rosen, Neal
• Format: Article
• Language: English
• ISSN: 1538-7445; 1538-7445
• DOI: 10.1158/1538-7445.AM2022-835

The majority of human breast cancers are dependent on Estrogen Receptor Alpha (ER) and sensitive to its inhibition. In advanced, ER+ dependent breast cancers, resistance usually develops and is associated with insensitivity of the estrogen receptor to inhibition. Mutations that activate PI3K signaling occur in over 40% of ER-driven breast cancers. The PI3K pathway regulates cap-dependent protein translation by controlling mTOR complex I (mTORC1). Inhibitors of PI3K/mTOR are effective in this setting when given with anti-estrogens, but induce ER activity and expression. We now show that despite reducing global cap-dependent translation, PI3K/mTOR inhibition does not reduce ER translation or expression. Translation of ER instead depends on the translation initiation factor, EIF4A. Inhibitors of EIF4A significantly reduce the expression of WT and mutant ER, with attendant blockage of breast cancer model growth in vivo, including models driven by estrogen-independent ER fusions that are unaffected by estrogen receptor antagonists. The utility of EIF4A inhibition can be enhanced when combined with Fulvestrant, a degrader of ER. Combining inhibition of ER translation and induction of ER degradation causes synergistic deep and durable inhibition of ER expression and tumor growth. Inhibition of ER translation represents a new potent strategy for treating ER-dependent breast cancers with acquired resistance to current therapies. Citation Format: Jacob A. Boyer, Madeline A. Dorso, Corina Amor, Jason Reiter, Jianing Xu, Elisa de Stanchina, Hans-Guido Wendel, Sarat Chandarlapaty, Neal Rosen. Estrogen receptor expression and ER dependent breast tumor growth are dependent on translation initiation factor EIF4A [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 835.