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

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.

The tetrameric structure of Plasmodium falciparum phosphoglycerate mutase is critical for optimal enzymatic activity

“…Interestingly, phosphoglycerate mutase is upregulated in different cancer types and is a potential drug target in cancer treatment [51,[65][66][67]. It is reported that the enzyme benefits tumor growth, increases the cellular life span and has the ability to immortalize the cells.…”

Emerging strategies to overcome resistance to third-generation EGFR inhibitors

“…HKB99 ( 103 ) (Fig. 14 ) is an allosteric inhibitor of PGAM1 that significantly inhibits the growth and metastasis of NSCLC by affecting the metabolic activity and nonmetabolic functions of PGAM1 [ 204 ]. The docking model of the PGAM1-HKB99 complex shows that HKB99 ( 103 ) binds to the allosteric site of the adjacent substrate-binding pocket of PGAM1, thereby inhibiting the conversion of 3-PG to 2-PG and significantly reducing the metabolic activity of PGAM1.…”

Targeting Energy Metabolism in Cancer Treatment

“…An in vitro study of the effect of HKB99 on non-small cell lung cancer (NSCLC), cells showed inhibition of proliferation and migration of cells and induction of apoptosis. Moreover, in vitro and in vivo studies with the use of xenografts have shown that HKB99 enhances the cytotoxic effect of erlotinib on NSCLC cells and overcomes the resistance to erlotinib [ 78 , 79 ]. One of the listed PGAM1 inhibitors is MJE3, but there are very limited scientific reports about its anti-cancer activity.…”