From the James Graham Brown Cancer Center, Division of Medical Oncology and Hematology, Department of Medicine, University of Louisville, Louisville, Kentucky 40202.
From the James Graham Brown Cancer Center, Division of Medical Oncology and Hematology, Department of Medicine, University of Louisville, Louisville, Kentucky 40202
J Biol Chem. 2019 Jul 5;294(27):10530-10543. doi: 10.1074/jbc.RA119.007784. Epub 2019 May 24.
Constitutive activation of the epidermal growth factor receptor (EGFR) because of somatic mutations of the gene is commonly observed in tumors of non-small cell lung cancer (NSCLC) patients. Consequently, tyrosine kinase inhibitors (TKI) targeting the EGFR are among the most effective therapies for patients with sensitizing EGFR mutations. Clinical responses to the EGFR-targeting TKIs are evaluated through 2-[F]fluoro-2-deoxy-glucose (FDG)-PET uptake, which is decreased in patients responding favorably to therapy and is positively correlated with survival. Recent studies have reported that EGFR signaling drives glucose metabolism in NSCLC cells; however, the precise downstream effectors required for this EGFR-driven metabolic effect are largely unknown. 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3) is an essential glycolytic regulator that is consistently overexpressed in lung cancer. Here, we found that PFKFB3 is an essential target of EGFR signaling and that PFKFB3 activation is required for glycolysis stimulation upon EGFR activation. We demonstrate that exposing NSCLC cells harboring either WT or mutated EGFR to EGF rapidly increases PFKFB3 phosphorylation, expression, and activity and that PFKFB3 inhibition markedly reduces the EGF-mediated increase in glycolysis. Furthermore, we found that prolonged NSCLC cell exposure to the TKI erlotinib drives PFKFB3 expression and that chemical PFKFB3 inhibition synergizes with erlotinib in increasing erlotinib's anti-proliferative activity in NSCLC cells. We conclude that PFKFB3 has a key role in mediating glucose metabolism and survival of NSCLC cells in response to EGFR signaling. These results support the potential clinical utility of using PFKFB3 inhibitors in combination with EGFR-TKIs to manage NSCLC.
表皮生长因子受体（EGFR）的组成性激活是由于基因的体细胞突变在非小细胞肺癌（NSCLC）患者的肿瘤中普遍观察到的。因此，针对 EGFR 的酪氨酸激酶抑制剂（TKI）是针对具有敏感 EGFR 突变的患者最有效的治疗方法之一。通过 2-[F]氟-2-脱氧葡萄糖（FDG）-PET 摄取来评估针对 EGFR 的靶向 TKI 的临床反应，在对治疗有良好反应的患者中，FDG 摄取减少，并且与生存呈正相关。最近的研究报告称，EGFR 信号驱动 NSCLC 细胞中的葡萄糖代谢；然而，这种 EGFR 驱动的代谢效应所必需的确切下游效应物在很大程度上仍是未知的。6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶（PFKFB3）是一种必需的糖酵解调节剂，在肺癌中始终过表达。在这里，我们发现 PFKFB3 是 EGFR 信号的必需靶标，并且 PFKFB3 的激活是 EGFR 激活后糖酵解刺激所必需的。我们证明，暴露于 EGF 的携带 WT 或突变 EGFR 的 NSCLC 细胞迅速增加 PFKFB3 磷酸化、表达和活性，并且 PFKFB3 抑制显著降低 EGF 介导的糖酵解增加。此外，我们发现，NSCLC 细胞长期暴露于 TKI 厄洛替尼会驱动 PFKFB3 表达，并且化学 PFKFB3 抑制与厄洛替尼协同作用，增加厄洛替尼在 NSCLC 细胞中的抗增殖活性。我们得出结论，PFKFB3 在介导 EGFR 信号对 NSCLC 细胞的葡萄糖代谢和存活中起关键作用。这些结果支持在管理 NSCLC 中使用 PFKFB3 抑制剂与 EGFR-TKI 联合的潜在临床应用。
