Pupo Emanuela, Avanzato Daniele, Middonti Emanuele, Bussolino Federico, Lanzetti Letizia
Department of Oncology, University of Torino Medical School, Turin, Italy.
Candiolo Cancer Institute, FPO-IRCCS, Turin, Italy.
Front Oncol. 2019 Aug 30;9:848. doi: 10.3389/fonc.2019.00848. eCollection 2019.
Tumors driven by mutant KRAS are among the most aggressive and refractory to treatment. Unfortunately, despite the efforts, targeting alterations of this GTPase, either directly or by acting on the downstream signaling cascades, has been, so far, largely unsuccessful. However, recently, novel therapeutic opportunities are emerging based on the effect that this oncogenic lesion exerts in rewiring the cancer cell metabolism. Cancer cells that become dependent on KRAS-driven metabolic adaptations are sensitive to the inhibition of these metabolic routes, revealing novel therapeutic windows of intervention. In general, mutant KRAS fosters tumor growth by shifting cancer cell metabolism toward anabolic pathways. Depending on the tumor, KRAS-driven metabolic rewiring occurs by up-regulating rate-limiting enzymes involved in amino acid, fatty acid, or nucleotide biosynthesis, and by stimulating scavenging pathways such as macropinocytosis and autophagy, which, in turn, provide building blocks to the anabolic routes, also maintaining the energy levels and the cell redox potential (1). This review will discuss the most recent findings on mutant KRAS metabolic reliance in tumor models of pancreatic and non-small-cell lung cancer, also highlighting the role that these metabolic adaptations play in resistance to target therapy. The effects of constitutive KRAS activation in glycolysis elevation, amino acids metabolism reprogramming, fatty acid turnover, and nucleotide biosynthesis will be discussed also in the context of different genetic landscapes.
由突变型KRAS驱动的肿瘤是最具侵袭性且最难治疗的肿瘤之一。不幸的是，尽管付出了诸多努力，但迄今为止，无论是直接靶向这种GTP酶的改变，还是作用于其下游信号级联反应，都在很大程度上未取得成功。然而，最近基于这种致癌性病变在重塑癌细胞代谢方面所发挥的作用，新的治疗机会正在出现。依赖KRAS驱动的代谢适应的癌细胞对这些代谢途径的抑制敏感，从而揭示了新的治疗干预窗口。一般来说，突变型KRAS通过将癌细胞代谢转向合成代谢途径来促进肿瘤生长。根据肿瘤类型的不同，KRAS驱动的代谢重塑通过上调参与氨基酸、脂肪酸或核苷酸生物合成的限速酶，以及刺激如巨胞饮作用和自噬等清除途径来实现，这些途径反过来为合成代谢途径提供构建模块，同时维持能量水平和细胞氧化还原电位（1）。本综述将讨论在胰腺癌和非小细胞肺癌肿瘤模型中关于突变型KRAS代谢依赖性的最新发现，同时强调这些代谢适应在靶向治疗耐药性中所起的作用。组成型KRAS激活在糖酵解升高、氨基酸代谢重编程、脂肪酸周转和核苷酸生物合成方面的影响也将在不同遗传背景的情况下进行讨论。
