磷酸甘油酸变位酶1（PGAM1）在EGFR突变型非小细胞肺癌代谢重编程中的调控作用

EGFR活化突变是非小细胞肺癌（NSCLC）常见的驱动基因，针对EGFR的靶向抑制药己成为一线治疗手段。磷酸甘油酸变位酶1（PGAM1）是肿瘤糖酵解关键酶，在肺癌代谢重编程中发挥关键作用。我们前期发现PGAM1新型变构抑制剂HKB99更显著抑制EGFR突变型肺癌细胞，提示EGFR突变型和野生型存在代谢异质性，调控通路机制值得进一步阐明。本项目拟采用EGFR突变过表达细胞、不同基因型细胞株和PDX等多个模型，抑制或过表达PGAM1，深入研究EGFR突变和PGAM1之间的关系；阐明EGFR突变型非小细胞肺癌高度依赖于PGAM1调控代谢重编程及与蛋白相互作用，获得恶性潜能并对EGFR-TKIs药物治疗产生耐药。研究成果将揭示PGAM1作为EGFR突变促进肺癌细胞恶性转化的核心效应分子，EGFR突变可指征靶向PGAM1药物治疗NSCLC的敏感性，为肺癌患者个体化治疗和联合用药方案提供实验理论依据。

Epidermal growth factor receptor (EGFR) is a predominant driver oncogene and therapeutic target mutated in high frequencies in non-small cell lung cancer (NSCLC). EGFR tyrosine kinase inhibitors (EGFR-TKIs) have been shown remarkable clinical benefit and consequently been approved as first-line precision therapies in NSCLC harboring somatic activating EGFR mutations. However, even if it is effective in the early treatment, the development of drug resistance is inevitable then leads to tumor metastasis and recurrence. Phosphoglycerate mutase 1 (PGAM1) plays a pivotal role in cancer metabolism and tumor progression, and is considered as an anti-cancer target. Our previous work has identified a novel PGAM1 allosteric inhibitor, HKB99, which suppressed tumor growth and metastasis, and overcame erlotinib resistance in NSCLC by impacting both PGAM1’s metabolic activity and non-metabolic function. Next, we will characterize the relationship of PGAM1 and EGFR mutation. The study will reveal that EGFR activation mutation preferentially depends on PGAM1 to branch glycolysis to the serine synthesis pathway and interaction with α–smooth muscle actin (ACTA2) during malignant transformation of NSCLC. EGFR mutation would be considered as a sensitive biomarker for targeting PGAM1 as a therapeutic strategy in NSCLC.