EGFR signaling through the PI3K pathway promotes tumor survival via SREBP1 mediated lipogenesis in glioblastoma patients

The EGFR/PI3K/Akt pathway is activated in many cancers including glioblastoma, clinical responses to EGFR inhibitors are infrequent and short-lived. Our group recent work targeting mTOR by Rapamycin in clinical trial may promote feedback activation leading to rapid time to clinical progression. These findings point to the plasticity of cancer cells in the face of targeted inhibition and suggest a need for developing new molecularly guided combination therapies to overcome it. AMPK is a metabolic checkpoint downstream of the LKB1 tumor suppressor that integrates growth factor receptor signaling with energy status. We found AMPK activation by AICAR is more effective than mTORC1 inhibition by Rapamycin for blocking the growth of EGFR-activated cancer cells. We demonstrate that enhanced efficacy is mediated by inhibition of cholesterol and fatty acid synthesis. 18F-FDG uptake assay using microPET/CT …