journal contribution posted on 2023-04-03, 15:02 authored by Yan Huang, Wei Hu, Jie Huang, Fangrong Shen, Yunjie Sun, Cristina Ivan, Sunila Pradeep, Robert Dood, Monika Haemmerle, Dahai Jiang, Lingegowda S. Mangala, Kyunghee Noh, Jean M. Hansen, Heather J. Dalton, Rebecca A. Previs, Archana S. Nagaraja, Michael McGuire, Nicholas B. Jennings, Russell Broaddus, Robert L. Coleman, Anil K. Sood
Supplementary Figure 1. In vitro effects of PR silencing on onapristone sensitivity in PR-high-expressing uterine cancer cell line (Ishikawa). Supplementary Figure 2. In vitro effects of onapristone and trametinib in PR-weak-expressing uterine cancer cell line (SKUT2). Supplementary Figure 3. In vivo effects of therapy with onapristone in uterine cancer model. Supplementary Figure 4. In vivo effect of onapristone, trametinib, and the combination of both drugs on total PR expression in the ISHIKAWA model.
Arno Therapeutics, Inc.
Frank McGraw Memorial Chair in Cancer Research
Ann Rife Cox Chair in Gynecology
MD Anderson Cancer Center
National Cancer Institute
Department of Health and Human Services
ARTICLE ABSTRACTAlthough progesterone receptor (PR)–targeted therapies are modestly active in patients with uterine cancer, their underlying molecular mechanisms are not well understood. The clinical use of such therapies is limited because of the lack of biomarkers that predict response to PR agonists (progestins) or PR antagonists (onapristone). Thus, understanding the underlying molecular mechanisms of action will provide an advance in developing novel combination therapies for cancer patients. Nuclear translocation of PR has been reported to be ligand-dependent or -independent. Here, we identified that onapristone, a PR antagonist, inhibited nuclear translocation of ligand-dependent or -independent (EGF) phospho-PR (S294), whereas trametinib inhibited nuclear translocation of EGF-induced phospho-PR (S294). Using orthotopic mouse models of uterine cancer, we demonstrated that the combination of onapristone and trametinib results in superior antitumor effects in uterine cancer models compared with either monotherapy. These synergistic effects are, in part, mediated through inhibiting the nuclear translocation of EGF-induced PR phosphorylation in uterine cancer cells. Targeting MAPK-dependent PR activation with onapristone and trametinib significantly inhibited tumor growth in preclinical uterine cancer models and is worthy of further clinical investigation. Mol Cancer Ther; 17(2); 464–73. ©2017 AACR.