Pancreatic cancer is a disease with limited therapeutic options. Resistance to chemotherapies poses a significant clinical challenge for patients with pancreatic cancer and contributes to a high rate of recurrence. Oncogenic KRAS, a critical driver of pancreatic cancer, promotes metabolic reprogramming and upregulates NRF2, a master regulator of the antioxidant network. Here, we show that NRF2 contributed to chemoresistance and was associated with a poor prognosis in patients with pancreatic cancer. NRF2 activation metabolically rewired and elevated pathways involved in glutamine metabolism. This curbed chemoresistance in KRAS-mutant pancreatic cancers. In addition, manipulating glutamine metabolism restrained the assembly of stress granules, an indicator of chemoresistance. Glutaminase inhibitors sensitized chemoresistant pancreatic cancer cells to gemcitabine, thereby improving the effectiveness of chemotherapy. This therapeutic approach holds promise as a novel therapy for patients with pancreatic cancer harboring KRAS mutation. SIGNIFICANCE: These findings illuminate the mechanistic features of KRAS-mediated chemoresistance and provide a rationale for exploiting metabolic reprogramming in pancreatic cancer cells to confer therapeutic opportunities that could be translated into clinical trials. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/8/1630/F1.large.jpg.

中文翻译：

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破坏谷氨酰胺分解可促进化疗，而 NRF2 可促进 KRAS 驱动的胰腺癌的化疗耐药性。


胰腺癌是一种治疗选择有限的疾病。对化疗的耐药性给胰腺癌患者带来了重大的临床挑战，并导致高复发率。致癌 KRAS 是胰腺癌的关键驱动因素，可促进代谢重编程并上调 NRF2（抗氧化网络的主要调节因子）。在这里，我们发现 NRF2 会导致化疗耐药，并与胰腺癌患者的不良预后相关。 NRF2 激活代谢重新连接并升高参与谷氨酰胺代谢的途径。这抑制了 KRAS 突变胰腺癌的化疗耐药性。此外，操纵谷氨酰胺代谢可以抑制应激颗粒的组装，应激颗粒是化学抗性的指标。谷氨酰胺酶抑制剂使化疗耐药的胰腺癌细胞对吉西他滨敏感，从而提高化疗的效果。这种治疗方法有望成为携带 KRAS 突变的胰腺癌患者的一种新疗法。意义：这些发现阐明了 KRAS 介导的化疗耐药的机制特征，并为利用胰腺癌细胞中的代谢重编程提供了可转化为临床试验的治疗机会的基本原理。图解摘要：http://cancerres.aacrjournals.org/content/canres/80/8/1630/F1.large.jpg。