4.8 Article

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

Journal

ADVANCED SCIENCE
Volume 10, Issue 7, Pages -

Publisher

WILEY
DOI: 10.1002/advs.202205262

Keywords

calcium; calmodulin-dependent protein kinase 2 isoform A; cancer stem cells; glutathione S-transferase pi; lung adenocarcinoma; nuclear factor erythroid 2-related factor 2

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GSTP1 is upregulated in lung cancer stem cells (CSCs) and plays a role in tumor self-renewal, metastasis, and resistance to treatment. The CaMK2A/NRF2/GSTP1 axis is identified as a regulatory pathway under hypoxia, where CaMK2A phosphorylates NRF2 to increase GSTP1 expression. Clinically, GSTP1 serves as a prognostic marker in lung adenocarcinoma (LUAD) and can be targeted for therapeutic purposes.
Glutathione S-transferase pi (GSTP1), a phase II detoxification enzyme, is known to be overexpressed and mediates chemotherapeutic resistance in lung cancer. However, whether GSTP1 supports cancer stem cells (CSCs) and the underlying mechanisms in lung adenocarcinoma (LUAD) remain largely unknown. This study unveiled that GSTP1 is upregulated in lung CSCs and supports tumor self-renewal, metastasis, and resistance to targeted tyrosine kinase inhibitors of LUAD both in vitro and in vivo. Mechanistically, CaMK2A (calcium/calmodulin-dependent protein kinase 2 isoform A)/NRF2 (nuclear factor erythroid 2-related factor 2)/GSTP1 is uncovered as a regulatory axis under hypoxia. CaMK2A increased GSTP1 expression through phosphorylating the Sersine558 residue of NRF2 and promoting its nuclear translocation, a novel mechanism for NRF2 activation apart from conventional oxidization-dependent activation. Upregulation of GSTP1 in turn suppressed reactive oxygen species levels and supported CSC phenotypes. Clinically, GSTP1 analyzed by immunohistochemistry is upregulated in a proportion of LUAD and serves as a prognostic marker for survival. Using patient-derived organoids from an ALK-translocated LUAD, the therapeutic potential of a specific GSTP1 inhibitor ezatiostat in combination treatment with the ALK inhibitor crizotinib is demonstrated. This study demonstrates GSTP1 to be a promising therapeutic target for long-term control of LUAD through targeting CSCs.

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