HKB99, an allosteric inhibitor of phosphoglycerate mutase 1, suppresses invasive pseudopodia formation and upregulates plasminogen activator inhibitor-2 in erlotinib-resistant non-small cell lung cancer cells
HKB99, an allosteric inhibitor of phosphoglycerate mutase 1, suppresses invasive pseudopodia formation and upregulates plasminogen activator inhibitor-2 in erlotinib-resistant non-small cell lung cancer cells
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HKB99 是磷酸甘油酸变位酶 1 的变构抑制剂，在厄洛替尼耐药的非小细胞肺癌细胞中抑制侵袭性伪足形成并上调纤溶酶原激活剂抑制剂 2
DOI：
10.1038/s41401-020-0399-1
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发表时间：
2020-05-13
影响因子：
8.2
通讯作者：
Shen, Ying
中科院分区：
文献类型：
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作者：
Liang, Qian;Gu, Wei-ming;Shen, Ying
对表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKIs)的获得性耐药，如厄洛替尼，仍然是非小细胞肺癌(NSCLC)靶向治疗的主要挑战。HKB99是一种新型的变构磷酸甘油酸变构酶1(PGAM1)抑制剂，与其亲本HCC827细胞相比，HKB99优先抑制获得性厄洛替尼耐药HCC827ER细胞的增殖并诱导更多的细胞凋亡。在这项研究中，我们确定了在对厄洛替尼耐药的HCC827ER细胞中HKB99反应的分子生物标记。我们发现HCC827ER细胞表现出增强的侵袭性伪足结构以及下调的纤溶酶原激活物抑制物-2(PAI-2)。同时，被siPAI-2候选基因敲除的PAI-2降低了HCC827亲本细胞对厄洛替尼的敏感性。此外，HKB99(5mU M)优先抑制HCC827ER细胞侵袭性伪足的形成，并增加PAI-2的水平。总之，这项研究为PAI-2在调节耐药非小细胞肺癌细胞对PGAM1抑制剂敏感性中的作用提供了新的见解。此外，PAI-2水平可作为预测PGAM1变构抑制剂对厄洛替尼耐药非小细胞肺癌细胞疗效的潜在生物标志物。
Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as erlotinib, remains a major challenge in the targeted therapy of non-small cell lung cancer (NSCLC). HKB99 is a novel allosteric inhibitor of phosphoglycerate mutase 1 (PGAM1) that preferentially suppresses cell proliferation and induces more apoptosis in acquired erlotinib-resistant HCC827ER cells compared with its parental HCC827 cells. In this study we identified the molecular biomarkers for HKB99 response in erlotinib-resistant HCC827ER cells. We showed that HCC827ER cells displayed enhanced invasive pseudopodia structures as well as downregulated plasminogen activator inhibitor-2 (PAI-2). Meanwhile, PAI-2 knockdown by siPAI-2 candidates decreased the sensitivity of HCC827 parental cells to erlotinib. Moreover, HKB99 (5 mu M) preferentially inhibited the invasive pseudopodia formation and increased the level of PAI-2 in HCC827ER cells. Collectively, this study provides new insight into the role of PAI-2 in regulating the sensitivity of erlotinib resistant NSCLC cells to PGAM1 inhibitor. Furthermore, PAI-2 level might be considered as a potential biomarker for predicting the efficacy of the PGAM1 allosteric inhibitor on the erlotinib resistant NSCLC cells.