Abstract 5759: Unraveling the roles of mTORC2 signaling in promoting aggressive glioblastoma characteristics through multi-omics analysis

The mechanistic target of rapamycin complex 2 (mTORC2) is a pivotal component of the mTOR signaling pathway, regulating critical cellular processes such as growth, proliferation, differentiation, survival, motility, and metabolism. Notably, mTORC2 facilitates actin cytoskeleton reorganization, cell motility, survival, and DNA damage repair. Aberrations in mTORC2 signaling are strongly associated with aggressive features of cancers, including glioblastoma (GBM), driving metastasis, drug resistance, recurrence, and tumor progression. However, unlike mTORC1, the molecular mechanisms governing mTORC2 functions remain less understood. To address this gap, we employed a comprehensive multi-omics approach—integrating transcriptomics, proteomics, phosphoproteomics, and interactomics—to investigate mTORC2-driven mechanisms underlying GBM aggressiveness. By leveraging computational big data analyses, we aimed to uncover therapeutic targets, identify biomarkers, and explore chemotherapy resistance mechanisms. Our findings reveal that mTORC2 signaling is intricately linked to key GBM hallmarks, including enhanced invasion, metastasis, genome instability, deregulated metabolism, and phenotypic plasticity. Disrupting mTORC2 profoundly altered intracellular regulatory mechanisms controlling these traits. Importantly, our analyses identified key molecular players driving these processes. Furthermore, we demonstrated that ATP-competitive inhibitors of mTOR kinase significantly enhanced the efficacy of temozolomide in GBM spheroid models, offering a promising strategy to overcome chemoresistance. These findings highlight the potential of targeting mTORC2-mediated pathways to develop more effective therapeutic strategies for aggressive cancers. Citation Format: Nuttiya Kalpongnukul, Rungnapa Bootsri, Gea A. Ecoy, Tankun Bunlue, Napatsakon Youngsanbhu, Chatchapon Chuenjit, Nuanwan Songcharoen, Trairak Pisitkun, Naphat Chantaravisoot. Unraveling the roles of mTORC2 signaling in promoting aggressive glioblastoma characteristics through multi-omics analysis [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 5759.