ENT1 blockade by CNX-774 overcomes resistance to DHODH inhibition in pancreatic cancer.
ENT1 blockade by CNX-774 overcomes resistance to DHODH inhibition in pancreatic cancer.
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DOI：
10.1016/j.canlet.2022.215981
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发表时间：
2023-01-01
期刊：
影响因子：
9.7
通讯作者：
Singh, Pankaj K.
中科院分区：
文献类型：
--
作者：
Mullen, Nicholas J.;Thakur, Ravi;Shukla, Surendra K.;Chaika, Nina, V;Kollala, Sai Sundeep;Wang, Dezhen;He, Chunbo;Fujii, Yuki;Sharma, Shikhar;Mulder, Scott E.;Sykes, David B.;Singh, Pankaj K.
关键词：
二氢乳清酸脱氢酶（DHODH）是嘧啶核苷酸从头合成的关键酶，尽管在临床前动物模型中具有强大的功效，但其抑制剂在各种癌症的临床试验中失败。为了探测DHODH抑制剂抗性的可药用介质，我们用小分子文库对对DHODH抑制剂布喹那（BQ）高度抗性的胰腺癌细胞系进行了组合筛选。筛选显示CNX-774，一种临床前布鲁顿酪氨酸激酶（BTK）抑制剂，使抗性细胞系对BQ敏感。机制研究表明，这种作用不依赖于BTK，而是由CNX-774抑制平衡型核苷转运蛋白1（ENT 1）引起的。我们表明，ENT 1介导的BQ电阻采取细胞外尿苷，这是抢救产生嘧啶核苷酸在DHODH独立的方式。在BQ抗性细胞系中，BQ单一疗法减缓增殖并引起适度的嘧啶核苷酸消耗，而BQ和CNX-774的组合治疗导致严重的细胞活力丧失和嘧啶饥饿。我们还确定N-乙酰神经氨酸积累作为DHODH抑制剂治疗效果的潜在标志物。在侵袭性免疫活性胰腺癌小鼠模型中，DHODH和ENT 1的联合靶向显著抑制肿瘤生长并延长小鼠存活。总的来说，我们的研究将CNX-774定义为以前未表征的ENT 1抑制剂，并为胰腺癌中DHODH和ENT 1的双重靶向提供了强有力的概念证据支持。
Inhibitors of dihydroorotate dehydrogenase (DHODH), a key enzyme for de novo synthesis of pyrimidine nucleotides, have failed in clinical trials for various cancers despite robust efficacy in preclinical animal models. To probe for druggable mediators of DHODH inhibitor resistance, we performed a combination screen with a small molecule library against pancreatic cancer cell lines that are highly resistant to the DHODH inhibitor brequinar (BQ). The screen revealed that CNX-774, a preclinical Bruton tyrosine kinase (BTK) inhibitor, sensitizes resistant cell lines to BQ. Mechanistic studies showed that this effect is independent of BTK and instead results from inhibition of equilibrative nucleoside transporter 1 (ENT1) by CNX-774. We show that ENT1 mediates BQ resistance by taking up extracellular uridine, which is salvaged to generate pyrimidine nucleotides in a DHODH-independent manner. In BQ-resistant cell lines, BQ monotherapy slowed proliferation and caused modest pyrimidine nucleotide depletion, whereas combination treatment with BQ and CNX-774 led to profound cell viability loss and pyrimidine starvation. We also identify N-acetylneuraminic acid accumulation as a potential marker of the therapeutic efficacy of DHODH inhibitors. In an aggressive, immunocompetent pancreatic cancer mouse model, combined targeting of DHODH and ENT1 dramatically suppressed tumor growth and prolonged mouse survival. Overall, our study defines CNX-774 as a previously uncharacterized ENT1 inhibitor and provides strong proof of concept support for dual targeting of DHODH and ENT1 in pancreatic cancer.
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影响因子：
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