| First Author | Liang J | Year | 2022 |
| Journal | Sci Transl Med | Volume | 14 |
| Issue | 663 | Pages | eabo5959 |
| PubMed ID | 36130016 | Mgi Jnum | J:335552 |
| Mgi Id | MGI:7439629 | Doi | 10.1126/scitranslmed.abo5959 |
| Citation | Liang J, et al. (2022) Giredestrant reverses progesterone hypersensitivity driven by estrogen receptor mutations in breast cancer. Sci Transl Med 14(663):eabo5959 |
| abstractText | 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 ERalpha, 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 ERalpha directly. These limitations, together with additional liabilities, inspired the development of the next generation of ERalpha-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 ERalpha-PR (progesterone receptor) cobinding at the promoter regions of pro-proliferation genes. PDX experiments showed that the mutant ERalpha-PR proliferative program is also relevant in human cancer cells. Giredestrant suppressed the mutant ERalpha-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 ERalpha can collaborate with PR to drive protumorigenic proliferation but remain sensitive to inhibition by giredestrant. |
