Abstract Despite advances in the treatment of breast cancer, it is still the second leading cause of cancer-related death in women worldwide. A large number of patients develop recurrence and die of advanced metastatic disease. More than 70% of metastatic breast cancers (mBC) express androgen receptor (AR) representing a potential target for anti-hormone therapies. AR is suggested to directly interact with an associated transcription factor (ARaTF) in breast cancer, however the functional role of ARaTF and its interaction with AR remains to be elucidated. We find that AR expression highly correlates with ARaTF in patients. To study its functional role driving tumorigenesis and metastatic outgrowth, we utilize patient-derived xenograft cell lines derived from liquid biopsies of mBC patients which reflect the highly heterogenous disease. Using genetically manipulated PDX cell models, we demonstrate that repression of ARaTF significantly reduces tumor growth of AR positive (AR+) BC cells in vivo. Notably, we observe the opposite phenotype in an AR negative cell model suggesting a tumor suppressive function when AR is not present. Mechanistically, we find that ARaTF regulates key metabolic processes: (1) Pharmacological inhibition of AR or silencing of ARaTF restricts mitochondrial respiration activity resulting in decreased energy production. (2) We also find that ARaTF positively regulates genes encoding enzymes involved in de novo fatty acid biosynthesis in AR+ BC. We further observe upregulation of the CD36 fatty acid transporter facilitating fatty acid uptake as compensatory pathway upon downregulation of ARaTF. Finally, abolishing CD36 expression in AR+ BC cells significantly reduces cell viability upon ARaTF downregulation. These findings suggest that lipid and energy metabolism are transcriptionally regulated by ARaTF facilitating cell survival in nutrient-depleted environments and thus facilitating metastatic outgrowth. These findings provide knowledge about the functional role of ARaTF regulating the lipogenic metabolic profile of AR+ breast cancer, and might help to identify patients who benefit from an anti-androgen treatment. Citation Format: Sarah-Jane Neuberth, Corinna Schumacher, Marteinn Thor Snaebjörnsson, Roberto Würth, Franziska Maria Zickgraf, Ornella Kossi, Felix Geist, Andrea Geist, Vera Thiel, Jonas Schwickert, Mattia Falcone, Massimo Saini, Almut Schulze, Andreas Trumpp, Martin R. Sprick. An androgen receptor-associated transcription factor regulates fatty acid metabolism driving tumor growth in androgen receptor-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 652.
Abstract Cancer types with lower mutational load and a non-permissive tumor microenvironment are intrinsically resistant to immune checkpoint blockade. While the combination of cytostatic drugs and immunostimulatory antibodies constitutes an attractive concept for overcoming this refractoriness, suppression of immune cell function by cytostatic drugs may limit therapeutic efficacy. Here we show that targeted inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) does not impair dendritic cell-mediated T cell priming and activation. Accordingly, combining MEK inhibitors (MEKi) with agonist antibodies (Abs) targeting the immunostimulatory CD40 receptor results in potent synergistic antitumor efficacy. Detailed analysis of the mechanism of action of MEKi shows that this drug exerts multiple pro-immunogenic effects, including the suppression of M2-type macrophages, myeloid derived suppressor cells and T-regulatory cells. The combination of MEK inhibition with agonist anti-CD40 Ab is therefore a promising therapeutic concept, especially for the treatment of mutant Kras-driven tumors such as pancreatic ductal adenocarcinoma.
