NSCLC is the leading cause of cancer mortality and represents a major challenge in cancer therapy. Intrinsic and acquired anticancer drug resistance are promoted by hypoxia and HIF-1α. Moreover, chemoresistance is sustained by the activation of key signaling pathways (such as RAS and its well-known downstream targets PI3K/AKT and MAPK) and several mutated oncogenes (including KRAS and EGFR among others). In this review, we highlight how these oncogenic factors are interconnected with cell metabolism (aerobic glycolysis, glutaminolysis and lipid synthesis). Also, we stress the key role of four metabolic enzymes (PFK1, dimeric-PKM2, GLS1 and ACLY), which promote the activation of these oncogenic pathways in a positive feedback loop. These four tenors orchestrating the coordination of metabolism and oncogenic pathways could be key druggable targets for specific inhibition. Since PFK1 appears as the first tenor of this orchestra, its inhibition (and/or that of its main activator PFK2/PFKFB3) could be an efficacious strategy against NSCLC. Citrate is a potent physiologic inhibitor of both PFK1 and PFKFB3, and NSCLC cells seem to maintain a low citrate level to sustain aerobic glycolysis and the PFK1/PI3K/EGFR axis. Awaiting the development of specific non-toxic inhibitors of PFK1 and PFK2/PFKFB3, we propose to test strategies increasing citrate levels in NSCLC tumors to disrupt this interconnection. This could be attempted by evaluating inhibitors of the citrate-consuming enzyme ACLY and/or by direct administration of citrate at high doses. In preclinical models, this “citrate strategy” efficiently inhibits PFK1/PFK2, HIF-1α, and IGFR/PI3K/AKT axes. It also blocks tumor growth in RAS-driven lung cancer models, reversing dedifferentiation, promoting T lymphocytes tumor infiltration, and increasing sensitivity to cytotoxic drugs.

非小细胞肺癌是癌症死亡的主要原因，是癌症治疗的主要挑战。缺氧和 HIF-1α 促进了内在和获得性抗癌药物耐药性。此外，化学抗性是通过激活关键信号通路（如 RAS 及其众所周知的下游靶点 PI3K/AKT 和 MAPK）和几个突变的癌基因（包括KRAS和EGFR等）来维持的。在这篇综述中，我们强调了这些致癌因素如何与细胞代谢（有氧糖酵解、谷氨酰胺分解和脂质合成）相互关联。此外，我们强调四种代谢酶（PFK1、二聚体-PKM2、GLS1 和 ACLY）的关键作用，它们在正反馈循环中促进这些致癌途径的激活。这四个男高音协调代谢和致癌途径可能是特异性抑制的关键药物靶点。由于 PFK1 是该管弦乐队的第一个男高音，它的抑制（和/或其主要激活剂 PFK2/PFKFB3 的抑制）可能是对抗 NSCLC 的有效策略。柠檬酸盐是 PFK1 和 PFKFB3 的强效生理抑制剂，NSCLC 细胞似乎维持低柠檬酸盐水平以维持有氧糖酵解和 PFK1/PI3K/EGFR 轴。在等待 PFK1 和 PFK2/PFKFB3 的特定无毒抑制剂的开发之前，我们建议测试增加 NSCLC 肿瘤中柠檬酸盐水平以破坏这种相互联系的策略。这可以通过评估消耗柠檬酸盐的酶 ACLY 的抑制剂和/或通过直接施用高剂量的柠檬酸盐来尝试。在临床前模型中，这种“柠檬酸盐策略”有效抑制 PFK1/PFK2、HIF-1α 和 IGFR/PI3K/AKT 轴。它还可以阻止 RAS 驱动的肺癌模型中的肿瘤生长，逆转去分化，促进 T 淋巴细胞肿瘤浸润，并增加对细胞毒性药物的敏感性。