Abstract B087: A systematic approach to JAK/STAT pathway shut-down

Janus Kinase Protein (JAK) plays a crucial role in a variety of intracellular mechanisms, and has been extensively studied for its role in proliferation and survival of cancer cells. One of the unique characteristics of this kinase is the variety of cell membrane receptors with which it is associated, and can trigger JAK activation process. Family of Signal Transducer and Activators of Transcription (STATs) are the direct downstream proteins that further transfer JAK signaling to the nucleus, which results in modification of expression level of a wide range of proteins. Triple-negative breast cancer (TNBC) represents one of the most aggressive and challenging subtypes of human breast cancer, due to lack of estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2) receptors, which renders the cells nonresponsive to hormone therapy. Several studies have confirmed that IL-6/gp130/JAK2/STAT3 signaling pathway is one of the crucial pathways that is implicated in TNBC development. However, monotherapies targeting JAK2 or STAT3 with molecularly targeted drugs have faced several challenges, including inherent and acquired resistance. Therefore, we aimed to determine feasibility and efficacy of therapy of TNBC using combinatorial silencing of different components in gp130/JAK2/STAT3 pathway. The downregulatory effects of siRNA targeting gp130, JAK2, STAT3, Importin α-3 alone or in combination were evaluated in human TNBC cells MDA 231 and MDA 468, and their effect on downstream targets involved in cell apoptosis and cell cycle were determined by real-time PCR and Western blot. The effect of individual and combinatorial silencing of the pathway components on cell proliferation and cell migration were also examined using CCK assay and Scratch assay, respectively. The siRNA treatment effectively reduced gene expression of gp130/JAK2/STAT pathway components at the mRNA level. Simultaneous inhibition of selected components significantly decreased TNBC cell proliferation rate. Moreover, combinatorial siRNA silencing inhibited the migration of TNBC cells. In conclusion, simultaneous inhibition of well-selected components of JAK/STAT pathway could represent an effective therapy for human TNBC. This warrants further in vivo study in animal models. Citation Format: Hamidreza Montazeri Aliabadi, Emira Bousoik, Parvin Mahdipoor. A systematic approach to JAK/STAT pathway shut-down [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B087.