STE029 Overcomes EGFR-TKI Resistance in Human Lung Adenocarcinoma.
10.3779/j.issn.1009-3419.2022.102.46
- Author:
Lin HUANG
1
;
Mei HOU
1
;
Jiewei LIU
1
;
Yang LI
2
;
Wang SHEN
1
;
Qinghua ZHOU
1
Author Information
1. Sichuan Lung Cancer Center, Sichuan Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu 610041, China.
2. Tianjin Key Laboratory of Lung Cancer, Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, China.
- Publication Type:Journal Article
- Keywords:
Apoptosis;
Cell cycle;
EGFR-TKI;
Lung adenocarcinoma;
Resistance;
STE029
- MeSH:
Animals;
Mice;
Humans;
Gefitinib/pharmacology*;
Caspase 9;
Caspase 8;
Cyclin D1;
Carcinoma, Non-Small-Cell Lung;
Glycogen Synthase Kinase 3 beta;
Mice, Nude;
Phosphatidylinositol 3-Kinases;
Proto-Oncogene Proteins c-akt;
Lung Neoplasms/genetics*;
Adenocarcinoma of Lung/drug therapy*;
Protein Kinase Inhibitors/pharmacology*;
ErbB Receptors/genetics*
- From:
Chinese Journal of Lung Cancer
2022;25(11):771-781
- CountryChina
- Language:Chinese
-
Abstract:
BACKGROUND:Acquired and primary resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is still the bottleneck of clinical treatment of advanced non-small cell lung cancer (NSCLC). STE029 is a novel anticancer drug which consists of 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMGCR) inhibitor and novel cancer cell membrane targeting molecular. This study aimed to investigate the reversal mechanism of EGFR-TKI resistance by STE029 in lung adenocarcinoma.
METHODS:CCK8 test was used to test the cell viability and survival rate of EGFR mutated PC9 cell (Gefitinib sensitive), PC9/BB4 cell (acquired Gefitinib resistant), and EGFR wild type A549 cell after treatment of STE029, Gefitinib or combination of both. EdU test was applied to detect changes in cell cycle and Hoechst 33258 was applied to detect apoptosis rate in overcoming the EGFR-TKI resistance. The activity of EGFR/PI3K/Akt, cell cycle and apoptosis signal pathways were examined. In vivo, nude mice were exposed to STE029, Gefitinib and STE029+Gefitinib for 5 wk. And the the tumor volume was measured and tumor weight was obtained on the last day.
RESULTS:(1) PC9 cells was highly sensitive to Gefitinib, while PC9/BB4 and A549 cell showed significant resistance to Gefitinib treatment; (2) STE029+Gefitinib treatment could significantly decrease the 50% inhibitory concentrarion (IC₅₀) of Gefitinib in PC9, PC9/BB4 and A549 cells (P<0.05, respectively); (3) In PC9 and PC9/BB4 cells, STE029+Gefitinib can block cell cycle and inhibit cell proliferation (P<0.001), while there was no significant difference in apoptosis rate among three drug intervention groups (P>0.05); However, apoptosis rate was increased in STE029+Gefitinib group in A549 cell (P<0.01), while no significance detected in cell proliferation (P>0.05). (4) In PC9 and PC9/BB4 cells, the combination of STE029 and Gefitinib could downregulate p-EGFR, p-Akt, p-Cyclin D1 and Cyclin D1 (P<0.001), and upregulate the expression of GSK-3β (P<0.001), and the expression of cleaved caspase-8, caspase-8 cleaved caspase-9, caspase-9 showed no difference among groups (P>0.05). In A549 cells, the combination of STE029 and Gefitinib could downregulate p-Akt (P<0.001) and upregulate cleaved caspase-8 and cleaved caspase-9 (P<0.001); (5)In vivo, the combination of STE029 and Gefitinib effectively inhibited tumor development and progression compared to STE029 alone or Gefitinib alone, with significant difference (P<0.05) in PC9 and PC9/BB4 xenografted tumor.
CONCLUSIONS:STE029 could sensitize Gefitinib by inhibiting EGFR/PI3K/Akt pathway, blocking the tumor cell cycle and proliferation and inducing apoptosis through caspase-8 and caspase-9 dependent pathway. STE029 deserves further investigations in overcoming EGFR-TKI resistance in lung cancer.
