An allosteric PGAM1 inhibitor effectively suppresses pancreatic ductal adenocarcinoma
An allosteric PGAM1 inhibitor effectively suppresses pancreatic ductal adenocarcinoma
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变构 PGAM1 抑制剂可有效抑制胰腺导管腺癌
DOI：
10.1073/pnas.1914557116
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发表时间：
2019-11-12
影响因子：
11.1
通讯作者：
Zhou, Lu
中科院分区：
文献类型：
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作者：
Wen, Chen-Lei;Huang, Ke;Zhou, Lu
胰腺导管腺癌是世界范围内最致命的恶性肿瘤之一，是胰腺癌的主要亚型。这促使我们在治疗中寻找调节肿瘤代谢的有效治疗靶点。通过发现磷酸甘油酸突变酶1 (PGAM1)，一种参与糖酵解和生物合成的关键代谢酶，在胰腺导管腺癌（PDAC）患者中经常上调，我们开发了一系列的变抗PGAM1抑制剂，这些抑制剂在多种PDAC临床前模型中显示有效，特别是PGAM1高表达的模型。值得注意的是，PGAM1抑制共同抑制了几种代谢和癌变途径，其中抑制水平与疗效相关。这项工作强烈表明，抑制癌症代谢可能是治疗胰腺癌的一种策略。糖酵解酶磷酸甘油酸突变酶1 （PGAM1）通过协调糖酵解和生物合成在肿瘤代谢中起关键作用。然而，一种有效的PGAM1抑制剂尚未被报道用于治疗胰腺导管腺癌（PDAC），这是世界上最致命的恶性肿瘤之一。在50例PDAC患者队列中，我们发现PGAM1表达升高与PDAC预后不良有统计学关系，我们通过结构导向优化开发了一系列变构PGAM1抑制剂。化合物KH3通过下调与PGAM1表达相关的糖酵解和线粒体呼吸水平，显著抑制多种PDAC细胞的增殖。与PGAM1缺失类似，KH3显著阻碍了高度参与癌症代谢和发展的基因通路。此外，我们在治疗后12小时观察到多个PDAC原代细胞中几种特征通路的共同表达谱，其中匹配的患者源异种移植（PDX）模型在治疗2周时与KH3反应相似。PDXs对KH3更好的应答与更高的PGAM1表达和更长/更强的癌症代谢途径抑制相关。综上所述，我们的研究结果证明了一种通过抑制PDAC中的PGAM1来靶向癌症代谢的策略。此外，这项工作为代谢治疗在临床实践中的潜在应用提供了“概念证明”。
Significance Dysregulated metabolism is one of the hallmarks of pancreatic ductal adenocarcinoma, which is the major subtype of pancreatic cancer considered as the deadliest malignancy worldwide. This led us to search the potent therapeutic target for regulating cancer metabolism in treatment. By uncovering that phosphoglycerate mutase 1 (PGAM1), a critical metabolic enzyme involved in glycolysis and biosynthesis, was frequently up-regulated in patients with pancreatic ductal adenocarcinoma (PDAC), we developed a series of allosteric PGAM1 inhibitors which showed efficacious in multiple preclinical models of PDAC, especially with high PGAM1 expression. Of note, PGAM1 inhibition cosuppressed several metabolic and cancerous pathways, of which the suppression level was correlated with efficacy. This work strongly suggests that inhibition of cancer metabolism would be a strategy for treating pancreatic cancer. Glycolytic enzyme phosphoglycerate mutase 1 (PGAM1) plays a critical role in cancer metabolism by coordinating glycolysis and biosynthesis. A well-validated PGAM1 inhibitor, however, has not been reported for treating pancreatic ductal adenocarcinoma (PDAC), which is one of the deadliest malignancies worldwide. By uncovering the elevated PGAM1 expressions were statistically related to worse prognosis of PDAC in a cohort of 50 patients, we developed a series of allosteric PGAM1 inhibitors by structure-guided optimization. The compound KH3 significantly suppressed proliferation of various PDAC cells by down-regulating the levels of glycolysis and mitochondrial respiration in correlation with PGAM1 expression. Similar to PGAM1 depletion, KH3 dramatically hampered the canonic pathways highly involved in cancer metabolism and development. Additionally, we observed the shared expression profiles of several signature pathways at 12 h after treatment in multiple PDAC primary cells of which the matched patient-derived xenograft (PDX) models responded similarly to KH3 in the 2 wk treatment. The better responses to KH3 in PDXs were associated with higher expression of PGAM1 and longer/stronger suppressions of cancer metabolic pathways. Taken together, our findings demonstrate a strategy of targeting cancer metabolism by PGAM1 inhibition in PDAC. Also, this work provided “proof of concept” for the potential application of metabolic treatment in clinical practice.