Activating mutations in KRAS (KRAS*) are present in nearly all pancreatic ductal adenocarcinoma (PDAC) cases and critical for tumor maintenance. By using an inducible KRAS* PDAC mouse model, we identified a deubiquitinase USP21-driven resistance mechanism to anti-KRAS* therapy. USP21 promotes KRAS*-independent tumor growth via its regulation of MARK3-induced macropinocytosis, which serves to maintain intracellular amino acid levels for anabolic growth. The USP21-mediated KRAS* bypass, coupled with the frequent amplification of USP21 in human PDAC tumors, encourages the assessment of USP21 as a novel drug target as well as a potential parameter that may affect responsiveness to emergent anti-KRAS* therapy.

中文翻译：

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USP21 去泛素酶提高巨胞饮作用，使胰腺癌中的致癌 KRAS 旁路成为可能

KRAS (KRAS*) 的激活突变几乎存在于所有胰腺导管腺癌 (PDAC) 病例中，对肿瘤维持至关重要。通过使用诱导型 KRAS* PDAC 小鼠模型，我们确定了一种去泛素酶 USP21 驱动的抗 KRAS* 治疗耐药机制。USP21 通过调节 MARK3 诱导的巨胞饮作用促进不依赖 KRAS* 的肿瘤生长，这有助于维持细胞内氨基酸水平以促进合成代谢生长。USP21 介导的 KRAS* 旁路，再加上人类 PDAC 肿瘤中 USP21 的频繁扩增，鼓励将 USP21 评估为一种新的药物靶点以及可能影响对紧急抗 KRAS* 治疗反应性的潜在参数。