Abstract 6668: MNK2-dependent activation of <i>de novo</i> lipid synthesis drives breast cancer brain metastasis

Patients with triple-negative breast cancer (TNBC) have poor prognosis, attributed to a ten-fold increased risk of developing brain metastases (compared to patients with other breast cancer subtypes), as well as the limited availability of effective therapies for breast cancer brain metastasis (BCBM). Recent work has revealed that SREBP1, a master transcription factor regulating de novo lipid synthesis, is required for BCBM survival in the lipid-depleted brain microenvironment. Given that previous studies have highlighted a link between MAPK interacting protein kinases (MNK) and lipid biosynthetic pathways, we investigated whether MNKs are essential for lipid biosynthesis in BCBM. We found that MNK2 and SREBP1 are upregulated in BCBM compared to paired primary cancers (n= 5 pairs, p&amp;lt;0.05). This upregulation is also observed in neurotropic 231-Br relative to its parental MDA-MB-231 TNBC cell line. Using a novel brain-penetrant MNK1/2 inhibitor, ETC-501, we show that MNK activity is required for growth of 231-Br cells in lipid-depleted conditions, as well as de novo lipid synthesis. Using a combination of immunofluorescence- and immunoblot-based assays, we find that ETC-501 prevents the nuclear translocation of SREBP1 and causes an accumulation of the precursor form of SREBP1 in the endoplasmic reticulum, preventing its processing into the mature form required for nuclear localization, and lipogenic gene activation. Importantly, we find that both genetic &amp; pharmacological inactivation of MNK prevents the establishment of BCBM in vivo. In rescue experiments, we find that expression of mature SREBP1c restores lipid droplet levels in ETC-501-treated cells. Our study reveals a critical role for MNK2 in regulating SREBP1 and lipid synthesis, providing new insights into TNBC BCBM. Inhibitors of MNK kinases, such as ETC-501, may offer potential in managing TNBC patients at high-risk for BCBM. Citation Format: Jessie Ling Ai Wong, Giselle Sek Suan Nah, Fatin Nasha Binte Sulaimi, Kian Leong Lee, Kassoum Nacro, Kaustubh Bhinge, Amanda E.D. Van Swearingen, Carey K. Anders, Sin Tiong Ong. MNK2-dependent activation of de novo lipid synthesis drives breast cancer brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6668.