Targeting GSTP1 as Therapeutic Strategy against Lung Adenocarcinoma Stemness and Resistance to Tyrosine Kinase...

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Glutathione S-transferase pi (GSTP1) is overexpressed in lung cancer, contributing to chemotherapy resistance.
• The role of GSTP1 in supporting lung adenocarcinoma cancer stem cells (CSCs) and its regulatory mechanisms are not well understood.

Purpose of the Study:

• To investigate the role of GSTP1 in lung adenocarcinoma CSCs.
• To elucidate the underlying molecular mechanisms of GSTP1 regulation in CSCs.
• To evaluate GSTP1 as a therapeutic target for lung adenocarcinoma.

Main Methods:

• In vitro and in vivo studies using lung adenocarcinoma models.
• Investigation of the CaMK2A/NRF2/GSTP1 signaling axis under hypoxia.
• Immunohistochemistry analysis of GSTP1 expression in patient samples.
• Treatment of patient-derived organoids with GSTP1 and ALK inhibitors.

Main Results:

• GSTP1 is upregulated in lung CSCs, promoting self-renewal, metastasis, and resistance to tyrosine kinase inhibitors.
• A novel hypoxia-induced CaMK2A/NRF2 pathway regulates GSTP1 via NRF2 phosphorylation and nuclear translocation.
• GSTP1 suppresses reactive oxygen species, maintaining CSC phenotypes.
• Upregulated GSTP1 is a prognostic marker for LUAD survival.
• Combination therapy with a GSTP1 inhibitor (ezatiostat) and ALK inhibitor (crizotinib) showed therapeutic potential in patient-derived organoids.

Conclusions:

• GSTP1 plays a critical role in supporting lung adenocarcinoma CSCs and mediating resistance.
• The CaMK2A/NRF2 pathway represents a novel mechanism for GSTP1 regulation in CSCs.
• Targeting GSTP1 is a promising strategy for the long-term control of lung adenocarcinoma by eliminating CSCs.