Imlunestrant is an Oral, Brain-Penetrant Selective Estrogen Receptor Degrader with Potent Antitumor Activity in ESR1 Wildtype and Mutant Breast Cancer.

Autor:	Bhagwat SV; Eli Lilly and Company, Indianapolis, Indiana, United States., Mur C; Eli Lilly and Company, Madrid, Spain., Vandekopple M; Eli Lilly and Company, Indianapolis, IN, United States., Zhao B; Eli Lilly and Company, Indianapolis, IN, United States., Shen W; Eli Lilly and Company, Indianapolis, Indiana, United States., Marugán C; Eli Lilly (Spain), Alcobendas, Madrid, Spain., Capen A; Eli Lilly and Company, Indianapolis, IN, United States., Kindler L; Eli Lilly and Company, Indianapolis, IN, United States., Stephens JR; Eli Lilly and Company, Indianapolis, Indiana, United States., Huber L; Eli Lilly and Company, Indianapolis, IN, United States., Castanares MA; Eli Lilly and Company, Indianapolis, IN, United States., Garcia-Tapia D; Eli Lilly and Company, Indianapolis, IN, United States., Cohen JD; Eli Lilly and Company, Indianapolis, IN, United States., Bastian J; Eli Lilly and Company, Indianapolis, IN, United States., Mattioni B; Eli Lilly and Company, Indianapolis, IN, United States., Yuen E; Eli Lilly and Company, United States., Baker TK; Eli Lilly and Company, United States., Rodriguez Cruz V; Eli Lilly and Company, United States., Fei D; Eli Lilly and Company, United States., Manro JR; Eli Lilly and Company, Indianapolis, IN, United States., Pulliam N; Eli Lilly and Company, Indianapolis, IN, United States., Dowless MS; Eli Lilly and Company, Indianapolis, Indiana, United States., Ortiz Ruiz MJ; Eli Lilly and Company, Madrid, Spain., Yu C; Lilly (China), Shanghai, Shanghai, China., Puca L; Eli Lilly (United States), New York, New York, United States., Klippel A; Eli Lilly and Company, New York City, New York, United States., Bacchion F; Eli Lilly and Company, Indianapolis, IN, United States., Ismail-Khan R; Eli Lilly and Company, Indianapolis, IN, United States., Rodrik-Outmezguine V; Eli Lilly and Company, Indianapolis, IN, United States., Peng SB; Eli Lilly and Company, Indianapolis, IN, United States., Lallena MJ; Eli Lilly and Company, Madrid, Spain., Gong X; Eli Lilly and Company, Indianapolis, Indiana, United States., de Dios A; Eli Lilly (United States), Indianapolis, United States.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2024 Dec 09. Date of Electronic Publication: 2024 Dec 09.
DOI:	10.1158/0008-5472.CAN-24-2608
Abstrakt:	Targeting of the estrogen receptor (ER) by anti-estrogens is the standard-of-care for patients with ER+ HER2- advanced/metastatic breast cancer. While anti-estrogens that degrade ERα (fulvestrant) or block estrogen production (aromatase inhibitors) have improved patient outcomes, clinically important challenges remain related to drug administration, limited bioavailability, lack of brain exposure, and acquired resistance due to ESR1 mutations. These limitations indicate a need for more robust ER-targeted therapies. Here, we discovered and characterized imlunestrant, a next-generation potent, brain-penetrant oral selective estrogen receptor degrader (SERD). Imlunestrant degraded ERα and decreased ERα-mediated gene expression both in vitro and in vivo. Cell proliferation and tumor growth in ESR1 wildtype and mutant models were significantly inhibited by imlunestrant. Combining imlunestrant with abemaciclib (CDK4/6 inhibitor), alpelisib (PI3K inhibitor), or everolimus (mTOR inhibitor) further enhanced tumor growth inhibition, regardless of ESR1 mutational status. In an ER+ breast cancer intracranial tumor model, imlunestrant prolonged survival compared to vehicle or alternative SERD therapies. Together, these finding support the potential of imlunestrant to degrade ERα and suppress the growth of ESR1 wildtype and mutant breast cancer, including brain metastatic tumors.
Databáze:	MEDLINE
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