1. Academic Validation
  2. 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

  • Acta Pharmacol Sin. 2021 Jan;42(1):115-119. doi: 10.1038/s41401-020-0399-1.
Qian Liang # 1 2 Wei-Ming Gu # 1 2 Ke Huang # 3 Ming-Yu Luo 1 2 Jing-Hua Zou 1 2 Guang-Lei Zhuang 4 Hui-Min Lei 1 2 Hong-Zhuan Chen 5 Liang Zhu 6 7 Lu Zhou 8 Ying Shen 9 10
Affiliations

Affiliations

  • 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.
  • 6 Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. [email protected].
  • 7 Shanghai Collaborative Innovation Center for Translational Medicine, Shanghai, 200025, China. [email protected].
  • 8 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China. [email protected].
  • 9 Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. [email protected].
  • 10 Shanghai Collaborative Innovation Center for Translational Medicine, Shanghai, 200025, China. [email protected].
  • # Contributed equally.
Abstract

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

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

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