eIF4A controls translation of estrogen receptor alpha and is a therapeutic target in advanced breast cancer

Abstract The majority of human breast cancers are dependent on hormone-stimulated estrogen receptor alpha (ER) and are sensitive to its inhibition. Treatment resistance arises in most advanced cancers due to genetic alterations that promote ligand independent activation of ER itself or ER target genes. Whereas re-targeting of the ER ligand binding domain (LBD) with newer ER antagonists can work in some cases, these drugs are largely ineffective in many genetic backgrounds including ER fusions that lose the LBD or in cancers that hyperactivate ER targets. By identifying the mechanism of ER translation, we herein present an alternative strategy to target ER and difficult to treat ER variants. We find that ER translation is cap-independent and mTOR inhibitor insensitive, but dependent on 5’ UTR elements and sensitive to pharmacologic inhibition of the translation initiation factor eIF4A, an mRNA helicase. EIF4A inhibition rapidly reduces expression of ER and short-lived targets of ER such as cyclin D1 and other components of the cyclin D-CDK complex in breast cancer cells. These effects translate into suppression of growth of a variety of ligand-independent breast cancer models including those driven by ER fusion proteins that lack the ligand binding site. The efficacy of eIF4A inhibition is enhanced when it is combined with fulvestrant—an ER degrader. Concomitant inhibition of ER synthesis and induction of its degradation causes synergistic and durable inhibition of ER expression and tumor growth. The clinical importance of these findings is confirmed by results of an early clinical trial (NCT04092673) of the selective eIF4A inhibitor zotatifin in patients with estrogen receptor positive metastatic breast cancer. Multiple clinical responses have been observed on combination therapy including durable regressions. These data suggest that eIF4A inhibition could be a useful new strategy for treating advanced ER+ breast cancer. Competing Interest Statement G.Y. and O.O. are listed as inventors in patents that were filed by MSKCC. O.O. receives royalties from some of the licensed patents. O.O. is an unpaid member of the SAB and owns shares of Angiogenex Therapeutics Inc. All are not related to this work. FP is a member of the scientific advisory board of MultiplexDX. In addition, FP serves on the diagnostic advisory board and reports receiving consultancy fees from AstraZeneca. S. Chandarlapaty reports personal fees from AstraZeneca, Daiichi-Sankyo, Effector, Nuvalent, Neogenomics, Genesis, Casdin Capital, Blueprint, grants from Daiichi-Sankyo and AstraZeneca and equity in Effector, Odyssey Bio, and Totus outside the submitted work. N.R. is on the scientific advisory board (SAB) and owns equity in Beigene, Zai Labs, MapKure, Ribon and Effector. N.R. is also on the SAB of Astra Zeneca and Chugai and a past SAB member of Novartis, Millennium-Takeda, Kura, and Araxes. N.R. is a consultant to RevMed, Tarveda, Array-Pfizer, Boehringer-Ingelheim and Eli Lilly. He receives research funding from Revmed, AstraZeneca, Array, Pfizer and Boehringer-Ingelheim and owns equity in Kura Oncology and Fortress. Footnotes ↵* Co-senior author