Blockage of EGFR/AKT and mevalonate pathways synergize the antitumor effect of temozolomide by reprogramming energy metabolism in glioblastoma

Abstract

BackgroundMetabolism reprogramming plays a vital role in glioblastoma (GBM) progression and recurrence by producing enough energy for highly proliferating tumor cells. In addition, metabolic reprogramming is crucial for tumor growth and immune‐escape mechanisms. Epidermal growth factor receptor (EGFR) amplification and EGFR‐vIII 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.MethodsClinical GBM specimens were selected for single‐cell RNA sequencing and untargeted metabolomics analysis. A metabolism‐associated RTK‐fatty acid‐gene signature was constructed and verified. MK‐2206 and MK‐803 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.ResultsGBM with high EGFR expression had characteristics of lipid remodeling and maintaining high cholesterol levels, supported by the single‐cell 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‐CoA synthetase short‐chain family member 3 (ACSS3), acyl‐CoA synthetase long‐chain family member 3 (ACSL3), and long‐chain fatty acid elongation‐related gene ELOVL fatty acid elongase 2 (ELOVL2) in an NF‐κB‐dependent 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.ConclusionsOur findings not only uncovered the mechanism of metabolic reprogramming in EGFR‐activated GBM but also provided a combinatorial therapeutic strategy for clinical GBM management.

Single cell sequencing revealed the mechanism of CRYAB in glioma and its diagnostic and prognostic value

“…Novel approaches such as targeted therapy and immunotherapy have emerged with the aim of interfering with specific signaling pathways in glioma cells or enhancing the immune system to suppress tumor growth. However, the immunosuppressive effects of glioma often contribute to poor treatment responses ( 50 ). The expression of CRYAB gene is mainly observed in cardiac and neural tissues, and its dysregulated expression has been linked to the pathogenesis and advancement of diverse immune-associated disorders ( 51 ).…”

Pro-Oxidant Auranofin and Glutathione-Depleting Combination Unveils Synergistic Lethality in Glioblastoma Cells with Aberrant Epidermal Growth Factor Receptor Expression

“…Investigating the impact of auranofin on EGFR-induced signaling showed that auranofin induced the ROS-dependent downregulation of EGFRvIII and Akt, two critical oncogenic signaling molecules involved in cell proliferation and survival [76,83]. EGFRinduced activation of PI3K/Akt pathway plays a key role in GBM cancer cell survival [76,84,85]. The primary function of Akt activation to control energy metabolism is coupled to inhibition of apoptosis, while uncontrolled cell cycle progression is promoted.…”

“…The primary function of Akt activation to control energy metabolism is coupled to inhibition of apoptosis, while uncontrolled cell cycle progression is promoted. Inhibition of the EGFR/Akt pathway inhibits mitochondrial function and decreases the expression of lipid metabolism-associated genes, leading to decreased ATP production [84]. Conversely, the hyperactivation of EGFR/Akt activates NF-κB-dependent transcriptional expression of lipid metabolism-associated genes in the U87/EGFRvIII cell line and a primary patient-derived EGFRvIII mutant GBM cell line [85].…”

Understanding the immunosuppressive microenvironment of glioma: mechanistic insights and clinical perspectives

“…AQP4's role in maintaining BBB integrity positions selective inhibition as a promising avenue for innovative therapies. PDGFRA amplification characterizes proneural subtypes, emphasizing its pivotal role [543][544][545]. Analysis of the database of TCGA and clinical samples reveals that elevated EPH receptor A2 (EPHA2) expression correlates with PDGF signaling pathway upregulation [151].…”