磷酸甘油酸脱氢酶（PHGDH）在肺腺癌EGFR-TKIs耐药性产生中的作用及其代谢重编程调控机制

Although the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as erlotinib, have shown dramatic effects against lung adenocarcinomas, patients become resistant by various mechanisms, including EGFR second mutation and bypass signaling reactive etc, thereafter relapsing. How to improve the efficacy and reverse the resistance to EGFR-TKIs remains a major challenge. Accumulating evidence has revealed that metabolic reprogramming played role in drug resistance. Phosphoglycerate dehydrogenase (PHGDH), a gatekeeper of the serine synthesis pathway (SSP), is associated with tumorigenesis and tumor progression. Nevertheless, the relationship between PHGDH and EGFR-TKIs resistance in lung adenocarcinomas remains largely unclear. Our previous work has found that the level of PHGDH increased significantly in the erlotinib resistant (ER) PC9ER4 and HCC827ER9 cells, compared to the parental sensitive cells respectively. Perturbation of PHGDH by siPHGDHs transfection restored sensitivity to erlotinib in PC9ER4 and HCC827ER9 cells in the complete medium. In this study, we will observe the effect of PHGDH on the erlotinib resistance in vitro and in vivo. The cell metabolic phenotypes, glucose metabolic flux, intermediate metabolites, reactive oxygen species (ROS) and related genes expression will be carefully determined. Collectively, our study will indicate that PHGDH promotes erlotinib resistance by regulating metabolic reprogramming via its SSP roles and interacting with other non-SSP genes like FOXM1. PHGDH inhibition has potential therapeutic value in lung adenocarcinomas with the acquisition of resistance to EGFR-TKIs.

Erlotinib等表皮生长因子受体-酪氨酸激酶抑制剂（EGFR-TKIs）靶向治疗肺腺癌疗效显著，但易耐药复发。已知耐药机制有靶基因突变、旁/下游通路代偿激活等，代谢重编程调控机制也引起越来越多的关注。磷酸甘油酸脱氢酶（PHGDH）是丝氨酸合成途径限速酶，与多种肿瘤的发生发展密切相关。我们前期工作发现肺腺癌耐Erlotinib细胞中PHGDH表达升高，下调PHGDH在完全营养条件下逆转耐药。本项目拟抑制或过表达PHGDH，开展体内外实验深入探讨PHGDH对肺腺癌细胞Erlotinib耐药性的影响；研究细胞代谢表型、葡萄糖代谢流、关键代谢产物、活性氧以及全基因组表达水平受PHGDH的调控，阐明PHGDH不仅通过丝氨酸合成途径，还能作用于FOXM1等基因，调控代谢重编程，介导细胞耐药。揭示PHGDH有望作为耐药靶标，提供新的靶向药物联合治疗策略，对肺腺癌个体化治疗具有重大临床意义。

Erlotinib等表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）靶向治疗肺腺癌疗效显著，但易耐药复发。已知耐药机制有靶基因突变、旁/下游通路代偿激活等，代谢重编程调控机制也引起越来越多的关注。磷酸甘油酸脱氢酶（PHGDH）是丝氨酸合成途径限速酶，与多种肿瘤的发生发展密切相关。我们前期工作已发现肺腺癌耐Erlotinib细胞（以下简称耐药细胞）中丝氨酸合成途径限速酶——磷酸甘油酸脱氢酶（PHGDH）及其合成产物丝氨酸含量明显上调；抑制PHGDH，在完全营养条件下能抑制耐药细胞增殖和肿瘤生长，诱导细胞凋亡，逆转耐药；反之则促进耐药发生；机制研究发现抑制PHGDH引起耐药细胞中DNA损伤，与PHGDH通过丝氨酸合成途径调控细胞内活性氧水平有关。本项目的顺利实施，揭示PHGDH作为肺腺癌耐药的潜在靶标，为PHGDH抑制剂联合EGFR-TKIs治疗克服单用EGFR-TKIs引起的耐药作用提供实验理论依据，对肺腺癌个体化治疗具有重大临床意义。