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

Authors: Qian Liang1,2, Wei-ming Gu1,2, Ke Huang3, Ming-yu Luo1,2, Jing-hua Zou1,2, Guang-lei Zhuang4, Hui-min Lei1,2, Hong-zhuan Chen5, Liang Zhu1,2, Lu Zhou3, Ying Shen1,2
1 Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
2 Shanghai Collaborative Innovation Center for Translational Medicine, Shanghai 200025, China
3 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China
4 State Key Laboratory of Oncogenes and Related Genes, Department of Obstetrics and Gynecology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200240, China
5 Institute of Interdisciplinary Integrative Biomedical Research, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
Correspondence to: Liang Zhu:, Lu Zhou:, Ying Shen:,
DOI: 10.1038/s41401-020-0399-1
Received: 5 January 2020
Accepted: 15 March 2020
Advance online: 13 May 2020


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 μM) 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.
Keywords: non-small cell lung cancer; erlotinib resistance; phosphoglycerate mutase 1; allosteric inhibitor; HKB99; plasminogen activator inhibitor-2

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