MYC/Glutamine Dependency Is a Therapeutic Vulnerability in Pancreatic Cancer with Deoxycytidine Kinase Inactivation-Induced Gemcitabine Resistance
MYC/Glutamine Dependency Is a Therapeutic Vulnerability in Pancreatic Cancer with Deoxycytidine Kinase Inactivation-Induced Gemcitabine Resistance
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DOI：
10.1158/1541-7786.mcr-22-0554
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发表时间：
2023-05-01
影响因子：
5.2
通讯作者：
Okada, Hitoshi
中科院分区：
文献类型：
--
作者：
Dash, Suman;Ueda, Takeshi;Okada, Hitoshi
胰腺导管腺癌（PDAC）是一种严重威胁生命的恶性肿瘤。虽然脱氧胞苷类似物吉西他滨已被用作PDAC的一线治疗，但由于最终获得耐药性，因此出现了主要的临床挑战。因此，阐明吉西他滨耐药的主要机制是至关重要的，并且DCKBA 2、DMBX 1、CROT和CD 36的失活轻微融合揭示了DCK KO细胞显示出与MYC靶点、叶酸/一碳代谢和谷氨酰胺代谢途径相关的基因的显著富集。显然，化学靶向这些途径中的每一个显著降低了DCK KO细胞的存活。此外，在DCK KO细胞中富集的途径代表了与PDAC细胞系和具有低DCK表达的PDAC患者样品中的那些途径相似的趋势。我们进一步观察到，用吉西他滨短期处理亲代CFPAC-1细胞会诱导几种基因的表达，这些基因以剂量依赖性方式促进谷氨酰胺的合成和转运，这表明谷氨酰胺的可用性是在最初的治疗中逃避药物毒性的潜在机制生存反应。因此，我们的研究结果为吉西他滨耐药PDAC的新治疗方法提供了见解，并强调了谷氨酰胺代谢在耐药持续细胞中的参与。
Pancreatic ductal adenocarcinoma (PDAC) is one of the most life-threatening malignancies. Although the deoxycytidine analog gemcitabine has been used as the first-line treatment for PDAC, the primary clinical challenge arises because of an eventual acquisition of resistance. Therefore, it is crucial to elucidate the mechanisms is the primary mechanism of gemcitabine resistance, and the inactivation of CRYBA2, DMBX1, CROT, and CD36 slightly conysis revealed that DCK KO cells displayed a significant enrichment of genes associated with MYC targets, folate/one-carbon metabolism and glutamine metabolism pathways. Evidently, chemically targeting each of these pathways significantly reduced the survival of DCK KO cells. Moreover, the pathways enriched in DCK KO cells represented a trend similar to those in PDAC cell lines and samples of patients with PDAC with low DCK expression. We further observed that short-term treatment of parental CFPAC-1 cells with gemcitabine induces the expression of several genes, which promote synthesis and transport of glutamine in a dose-dependent manner, which suggests glutamine availability as a potential mechanism of escaping drug toxicity in an initial response for survival. Thus, our findings provide insights into novel therapeutic approaches for gemcitabine-resistant PDAC and emphasize the involvement of glutamine metabolism in drug-tolerant persister cells.