IQGAP3 bridges matrix stiffness with cancer stem cell maintenance and radioresistance by stabilizing SOX2

Drivers of therapeutic resistance in cancer include evolution of tumor cell heterogeneity and the tumor microenvironment (TME). Here, we found that increased matrix stiffness promotes radioresistance in glioblastoma (GBM) and maintains the tumor cell hierarchy. Differential gene expression revealed that stiff matrices induced expression of IQGAP3 (IQ Motif Containing GTPase Activating Protein 3) specifically in GBM stem cells (GSCs). IQGAP3 promoted GSC self-renewal and survival upon radiation treatment through binding and stabilization of the core stem cell transcription factor, SOX2. Targeting IQGAP3 reduced SOX2 protein levels in vitro and in vivo, increasing GSC radiosensitivity and inhibiting tumor growth. Structure-function drug screening of FDA-approved agents blocking IQGAP3 binding to SOX2 identified Trimetrexate as a brain penetrant pharmacologic disruptor of IQGAP3 function in radioresistance, sensitizing GSCs to radiotherapy. Our results identify molecular underpinnings for biomechanical promotion of cancer stem cell maintenance and therapeutic resistance, informing a therapeutic strategy to augment efficacy of radiotherapy.