Bibliographic Details
| Title: |
Giredestrant reverses progesterone hypersensitivity driven by estrogen receptor mutations in breast cancer. |
| Authors: |
Liang, Jackson, Ingalla, Ellen Rei, Yao, Xiaosai, Wang, Bu-Er, Tai, Lisa, Giltnane, Jennifer, Liang, Yuxin, Daemen, Anneleen, Moore, Heather M., Aimi, Junko, Chang, Ching-Wei, Gates, Mary R., Eng-Wong, Jennifer, Tam, Lucinda, Bacarro, Natasha, Roose-Girma, Merone, Bellet, Meritxell, Hafner, Marc, Metcalfe, Ciara |
| Source: |
Science Translational Medicine; 9/21/2022, Vol. 14 Issue 663, p1-12, 12p |
| Subject Terms: |
ESTROGEN receptors, PROGESTERONE, BREAST cancer, PROGESTERONE receptors, MAMMARY glands, TISSUE remodeling |
| Abstract: |
ESR1 (estrogen receptor 1) hotspot mutations are major contributors to therapeutic resistance in estrogen receptor–positive (ER+) breast cancer. Such mutations confer estrogen independence to ERα, providing a selective advantage in the presence of estrogen-depleting aromatase inhibitors. In addition, ESR1 mutations reduce the potency of tamoxifen and fulvestrant, therapies that bind ERα directly. These limitations, together with additional liabilities, inspired the development of the next generation of ERα-targeted therapeutics, of which giredestrant is a high-potential candidate. Here, we generated Esr1 mutant–expressing mammary gland models and leveraged patient-derived xenografts (PDXs) to investigate the biological properties of the ESR1 mutations and their sensitivity to giredestrant in vivo. In the mouse mammary gland, Esr1 mutations promote hypersensitivity to progesterone, triggering pregnancy-like tissue remodeling and profoundly elevated proliferation. These effects were driven by an altered progesterone transcriptional response and underpinned by gained sites of ERα-PR (progesterone receptor) cobinding at the promoter regions of pro-proliferation genes. PDX experiments showed that the mutant ERα-PR proliferative program is also relevant in human cancer cells. Giredestrant suppressed the mutant ERα-PR proliferation in the mammary gland more so than the standard-of-care agents, tamoxifen and fulvestrant. Giredestrant was also efficacious against the progesterone-stimulated growth of ESR1 mutant PDX models. In addition, giredestrant demonstrated activity against a molecularly characterized ESR1 mutant tumor from a patient enrolled in a phase 1 clinical trial. Together, these data suggest that mutant ERα can collaborate with PR to drive protumorigenic proliferation but remain sensitive to inhibition by giredestrant. Engaging ESR1 mutant tumors: Breast cancers often express estrogen receptor–α (ERα), which represents vulnerability for targeted treatment using ERα-directed therapies. However, because of their very nature, these targeted therapies lead to acquired resistance, requiring the development of next-generation ERα-targeted therapies such as giredestrant. Here, Liang et al. leveraged the mouse mammary gland to examine altered ERα signaling caused by mutations in estrogen receptor 1 (ESR1) and evaluated the effectiveness of giredestrant against ESR1 mutant patient-derived xenografts. They saw that mutant ERα and progesterone drive tumorigenicity, but tumors with these alterations remain sensitive to giredestrant, representing a promising therapy to overcome acquired resistance. [ABSTRACT FROM AUTHOR] |
|
Copyright of Science Translational Medicine is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) |
| Database: |
Complementary Index |
