Different evidence has indicated metabolic rewiring as a necessity for pancreatic cancer (PC) growth, invasion, and chemotherapy resistance. A relevant role has been assigned to glucose metabolism. In particular, an enhanced flux through the Hexosamine Biosynthetic Pathway (HBP) has been tightly linked to PC development. Here, we show that enhancement of the HBP, through the upregulation of the enzyme Phosphoacetylglucosamine Mutase 3 (PGM3), is associated with the onset of gemcitabine (GEM) resistance in PC. Indeed, mRNA profiles of GEM sensitive and resistant patient-derived tumor xenografts (PDXs) indicate that PGM3 expression is specifically increased in GEM-resistant PDXs. Of note, PGM3 results also overexpressed in human PC tissues as compared to paired adjacent normal tissues and its higher expression in PC patients is associated with worse median overall survival (OS). Strikingly, genetic or pharmacological PGM3 inhibition reduces PC cell growth, migration, invasion, in vivo tumor growth and enhances GEM sensitivity. Thus, combined treatment between a specific inhibitor of PGM3, named FR054, and GEM results in a potent reduction of xenograft tumor growth without any obvious side effects in normal tissues. Mechanistically, PGM3 inhibition, reducing protein glycosylation, causes a sustained Unfolded Protein Response (UPR), a significant attenuation of the pro-tumorigenic Epidermal Growth Factor Receptor (EGFR)-Akt axis, and finally cell death. In conclusion this study identifies the HBP as a metabolic pathway involved in GEM resistance and provides a strong rationale for a PC therapy addressing the combined treatment with the PGM3 inhibitor and GEM.

中文翻译：

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己糖胺通路抑制通过未折叠蛋白反应和 EGFR-Akt 通路调节克服了胰腺癌对吉西他滨的耐药性。

不同的证据表明代谢重新布线是胰腺癌 (PC) 生长、侵袭和化疗耐药性的必要条件。已将相关作用分配给葡萄糖代谢。特别是，通过己糖胺生物合成途径 (HBP) 的通量增强与 PC 开发密切相关。在这里，我们表明通过上调磷酸乙酰氨基葡萄糖变位酶 3 (PGM3) 来增强 HBP 与 PC 中吉西他滨 (GEM) 耐药性的发生有关。事实上，GEM 敏感和耐药患者衍生的肿瘤异种移植物 (PDX) 的 mRNA 谱表明 PGM3 表达在 GEM 耐药 PDX 中特异性增加。值得注意的是，与配对的相邻正常组织相比，PGM3 结果在人类 PC 组织中也过表达，并且其在 PC 患者中的较高表达与较差的中位总生存期 (OS) 相关。引人注目的是，遗传或药理学 PGM3 抑制可减少 PC 细胞生长、迁移、侵袭、体内肿瘤生长并增强 GEM 敏感性。因此，一种名为 FR054 的 PGM3 特异性抑制剂与 GEM 的联合治疗可有效减少异种移植肿瘤的生长，而对正常组织没有任何明显的副作用。从机制上讲，PGM3 抑制，减少蛋白质糖基化，导致持续的未折叠蛋白质反应 (UPR)，促肿瘤表皮生长因子受体 (EGFR)-Akt 轴的显着减弱，最后导致细胞死亡。