Differential pathway activation can be detected and tested for significance with our network enrichment analysis tool (NEA). In this project, we studied tumor response to treatment with a candidate drug, VPS34 inhibitor SB02024 in the Renca mouse model. Even though the conventional differential expression analysis of data from the NanoString transcriptomics assay did not bring significant discoveries, the application of NEA was successful. When the transcriptome alterations were presented as sets of 30 most altered genes, NEA could demonstrate that the pathways most relevant to SB02024 action (STING-mediated, interferon, cytokine and chemokine signaling) were indeed strongly affected. Canonical IFN signaling activated STAT pathway and transcription of IFN-stimulated genes, some of which turn to be involved in the proinflammatory cytokine response induced by SB02024.
Yasmin Yu, Madhumita Bogdan, Muhammad Zaeem Noman, Santiago Parpal, Elisabetta Bartolini, Kris Van Moer, Simone Caroline Kleinendorst, Kristine Bilgrav Saether, Lionel Trésaugues, Camilla Silvander, Johan Lindström, Jodi Simeon, Mary Jane Timson, Hikmat Al-Hashimi, Bryan D. Smith, Daniel L. Flynn, Andrey Alexeyenko, Jenny Viklund, Martin Andersson, Jessica Martinsson, Katja Pokrovskaja Tamm, Angelo De Milito, Bassam Janji Combining VPS34 inhibitors with STING agonists enhances type I IFN signaling and anti-tumor efficacy. Molecular Oncology, 20 March 2024
