breast cancer; endocrine therapy; hormone receptor positive; immune checkpoint inhibitor; targeted therapy; Receptors, Estrogen; Fulvestrant; Immune Checkpoint Inhibitors; Animals; Female; Rats; Rats, Sprague-Dawley; Fulvestrant/pharmacology; Disease Models, Animal; Immune Checkpoint Inhibitors/pharmacology; Immune Checkpoint Inhibitors/therapeutic use; Humans; Breast Neoplasms/drug therapy; Breast Neoplasms/immunology; Breast Neoplasms/metabolism; Breast Neoplasms/pathology; Breast Neoplasms/genetics; Receptors, Estrogen/metabolism; Immunotherapy/methods; Mammary Neoplasms, Experimental/drug therapy; Breast Neoplasms; Immunotherapy; Mammary Neoplasms, Experimental; Multidisciplinary
Abstract :
[en] Estrogen receptor (ER) positive breast cancer is the most prevalent subtype, commonly responsive to endocrine therapies. Immune checkpoint inhibitors (ICIs) have limited efficacy in ER-positive disease, highlighting the need for the development of combination immunotherapies for these patients. We previously established that nitroso-N-methylurea-induced mammary tumors in outbred Sprague-Dawley rats mimic immune evasive mechanisms and the heterogeneity of ICI response observed in patients. We identified a "luminal growing" gene signature in ER-positive tumors, which correlated with tumor growth and immune-related differences. Here, we evaluated targeting candidates from this signature KMT5B/C and IKBKE using inhibitors A-196 and IKBKEi respectively, alongside anti-estrogen (fulvestrant) and a TGFβ blocking antibody (NIS793), both individually and in combination with αPD-L1, within this rat model. Fulvestrant emerged as the most effective treatment, inducing regression of most existing tumors and reducing on-treatment tumor burden when combined with αPD-L1. A-196, while ineffective as a monotherapy, demonstrated enhanced response when combined with αPD-L1. Comprehensive tumor profiling through polychromatic flow cytometry and single-cell RNA sequencing revealed that A-196 induced a luminal-to-basal shift in tumor epithelial cells, enhancing antigen presentation, whereas epithelial-to-mesenchymal transition was linked to fulvestrant resistance. Our findings underscore the value of the rat mammary tumor model for preclinical studies in ER-positive breast cancer and advocate for the further validation and potential clinical development of KMT5B/C inhibitors to enhance the efficacy and broaden the applicability of ICI therapy in cancer patients.
Disciplines :
Oncology
Author, co-author :
Rojas-Jimenez, Ernesto; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215 ; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 ; Department of Medicine, Harvard Medical School, Boston, MA 02115
Bui, Triet M; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215 ; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 ; Department of Medicine, Harvard Medical School, Boston, MA 02115
Yan, Pengze ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215 ; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 ; Department of Medicine, Harvard Medical School, Boston, MA 02115
Li, Zheqi; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215 ; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 ; Department of Medicine, Harvard Medical School, Boston, MA 02115
Seehawer, Marco; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215 ; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 ; Department of Medicine, Harvard Medical School, Boston, MA 02115
Nishida, Jun ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215 ; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 ; Department of Medicine, Harvard Medical School, Boston, MA 02115
Foidart, Pierre ; Université de Liège - ULiège > Département des sciences cliniques ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'oncologie médicale ; Université de Liège - ULiège > Département des sciences cliniques > Oncologie ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215 ; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 ; Department of Medicine, Harvard Medical School, Boston, MA 02115
Freeman, Gordon J ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215 ; Department of Medicine, Harvard Medical School, Boston, MA 02115
Polyak, Kornelia ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215 ; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 ; Department of Medicine, Harvard Medical School, Boston, MA 02115
Language :
English
Title :
Evaluation of targeted and immune combination therapies in a rat model of hormone receptor-positive breast cancer.
Publication date :
10 February 2026
Journal title :
Proceedings of the National Academy of Sciences of the United States of America
NIH. NCI - National Institutes of Health. National Cancer Institute NIH - National Institutes of Health BCRF - Breast Cancer Research Foundation Novartis
Funding text :
We thank members of our laboratory for their critical reading of this manuscript and insightful discussions. This research was supported by the Novartis Institute for Biomedical Research (K.P.), National Cancer Institute T32 CA236754 (T.M.B.), NIH P01 AI056299 (G.J.F.), Charles King Foundation (Z.L.), Belgian American Educational Foundation (P.F.), and the Breast Cancer Research Foundation (K.P.). K.P. receives sponsored research funding through Dana-Farber from Novartis that in part funded this study.
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