Abstract 435: JAK/STAT1-interferon-ISGylation networks in breast cancer resistance to inhibitors of FOXM1 and CDK4/6

Abstract Resistance to targeted therapies often develops in advanced estrogen receptor (ER)-positive breast cancer, but the mechanisms underlying this resistance are still not fully known. We show that ER-positive FOXM1 inhibitor resistant cells and CDK4/6 inhibitor (Palbociclib and Abemaciclib) resistant cells all exhibit an increased JAK/STAT1-interferon responsive gene and protein signaling network with elevated interferon stimulated gene15 (ISG15). ISG15 protein is present as high intracellular free ISG15 and also as increased ISGylated protein conjugates that can be markedly reduced by treatment of resistant cells with the JAK1/2 inhibitor ruxolitinib. Likewise, resistant cells contain increased levels of ubiquitin-like conjugating enzymes HERC5 and HERC6 and ubiquitin ligases (e.g., UBE2L6) known to facilitate the transfer of ISG15 onto cell proteins. Notably, elevated ISG15 and elevated HERC5 and HERC6 are all associated with poorer relapse-free and overall patient survival. Breast cancer cells resistant to the CDK4/6 inhibitors Palbo or Abema, which are often used in first line treatment of patients with HR-positive breast cancer, and cells resistant to FOXM1 inhibitor show some similarities in the ISGylated protein patterns. However, there are also some differences observed in these patterns between Palbo and Abema and FOXM1 inhibitor (NB73) resistant cells. Upregulation of this STAT1-interferon-ISGylation network in ER-positive breast cancers displaying resistance to three different drugs suggests it may be centrally involved in supporting the drug-resistant state. Importantly, Palbo and Abema resistant cells and organoids can still be effectively growth inhibited by FOXM1 inhibitor NB73, and likewise, FOXM1 inhibitor resistant cells and organoids are sensitive to suppression of viability by Palbo or Abema. This suggests that sequential treatment approaches might be effective in overcoming resistance and enabling the suppression of these drug-resistant cancers.(Supported by Breast Cancer Research Foundation grant BCRF-083 and NIH R01CA220284 to BSK and BCRF grant BCRF-145 to RS) Citation Format: Benita S. Katzenellenbogen, Yvonne Ziegler, Sandeep Kumar, Blake N. Plotner, Carlos M. Saeh, Grace O. Pento, Sung Hoon Kim, Rachel Schiff, John A. Katzenellenbogen. JAK/STAT1-interferon-ISGylation networks in breast cancer resistance to inhibitors of FOXM1 and CDK4/6 [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 435.