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In addition, metabolic reprogramming is crucial for tumor growth and immune\u2010escape mechanisms. Epidermal growth factor receptor (\n                      <jats:italic toggle=\"yes\">EGFR<\/jats:italic>\n                      ) amplification and\n                      <jats:italic toggle=\"yes\">EGFR\u2010vIII<\/jats:italic>\n                      mutation are often detected in GBM cells, contributing to the malignant behavior. This study aimed to investigate the functional role of the EGFR pathway on fatty acid metabolism remodeling and energy generation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">Clinical GBM specimens were selected for single\u2010cell RNA sequencing and untargeted metabolomics analysis. A metabolism\u2010associated RTK\u2010fatty acid\u2010gene signature was constructed and verified. MK\u20102206 and MK\u2010803 were utilized to block the RTK pathway and mevalonate pathway induced abnormal metabolism. Energy metabolism in GBM with activated EGFR pathway was monitored. The antitumor effect of Osimertinib and Atorvastatin assisted by temozolomide (TMZ) was analyzed by an intracranial tumor model in vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">GBM with high EGFR expression had characteristics of lipid remodeling and maintaining high cholesterol levels, supported by the single\u2010cell RNA sequencing and metabolomics of clinical GBM samples. Inhibition of the EGFR\/AKT and mevalonate pathways could remodel energy metabolism by repressing the tricarboxylic acid cycle and modulating ATP production. Mechanistically, the EGFR\/AKT pathway upregulated the expressions of acyl\u2010CoA synthetase short\u2010chain family member 3 (ACSS3), acyl\u2010CoA synthetase long\u2010chain family member 3 (ACSL3), and long\u2010chain fatty acid elongation\u2010related gene ELOVL fatty acid elongase 2 (ELOVL2) in an NF\u2010\u03baB\u2010dependent manner. Moreover, inhibition of the mevalonate pathway reduced the EGFR level on the cell membranes, thereby affecting the signal transduction of the EGFR\/AKT pathway. Therefore, targeting the EGFR\/AKT and mevalonate pathways enhanced the antitumor effect of TMZ in GBM cells and animal models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">Our findings not only uncovered the mechanism of metabolic reprogramming in EGFR\u2010activated GBM but also provided a combinatorial therapeutic strategy for clinical GBM management.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cac2.12502","type":"journal-article","created":{"date-parts":[[2023,11,3]],"date-time":"2023-11-03T01:44:35Z","timestamp":1698975875000},"page":"1326-1353","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":62,"title":["Blockage of EGFR\/AKT and mevalonate pathways synergize the antitumor effect of temozolomide by reprogramming energy metabolism in glioblastoma"],"prefix":"10.34133","volume":"43","author":[{"given":"Xiaoteng","family":"Cui","sequence":"first","affiliation":[{"name":"Tianjin Medical University General Hospital","place":["Tianjin, P. 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