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

by Selleckchem | Nov 07 2023

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.

Comments:

The study you mentioned investigates the role of Glutathione S-transferase pi (GSTP1) in lung adenocarcinoma (LUAD), specifically focusing on its association with cancer stem cells (CSCs), tumor self-renewal, metastasis, and resistance to targeted therapies. Here are the key findings and implications of the study:

1. GSTP1 upregulation in lung CSCs: The study reveals that GSTP1 is overexpressed in lung CSCs, suggesting its involvement in maintaining the CSC population in LUAD.

2. Tumor self-renewal, metastasis, and drug resistance: GSTP1 supports tumor self-renewal, facilitates metastatic processes, and contributes to resistance against targeted tyrosine kinase inhibitors used in LUAD treatment. This implies that GSTP1 plays a significant role in the aggressive behavior and therapeutic resistance of LUAD.

3. CaMK2A/NRF2/GSTP1 regulatory axis: The study identifies a regulatory axis involving CaMK2A (calcium/calmodulin-dependent protein kinase 2 isoform A), NRF2 (nuclear factor erythroid 2-related factor 2), and GSTP1 under hypoxic conditions. CaMK2A phosphorylates the Serine558 residue of NRF2, promoting its nuclear translocation and leading to increased GSTP1 expression. This mechanism represents a novel pathway for NRF2 activation independent of the conventional oxidization-dependent activation.

4. Suppression of reactive oxygen species (ROS) and CSC phenotypes: Upregulated GSTP1 in LUAD reduces ROS levels, thereby supporting CSC phenotypes. This suggests that GSTP1 contributes to the maintenance of CSC characteristics by modulating intracellular ROS levels.

5. Prognostic marker: Immunohistochemical analysis reveals that GSTP1 is upregulated in a subset of LUAD cases. The study suggests that GSTP1 expression can serve as a prognostic marker for survival, potentially helping to predict patient outcomes.

6. Therapeutic potential: Using patient-derived organoids from an LUAD with ALK translocation, the study demonstrates the therapeutic potential of a specific GSTP1 inhibitor called ezatiostat. Combination treatment of ezatiostat with the ALK inhibitor crizotinib shows promise in inhibiting LUAD growth, suggesting a potential strategy for targeting GSTP1 in combination with other therapies.

Overall, this study highlights the significance of GSTP1 in LUAD progression, CSC maintenance, metastasis, and drug resistance. Targeting GSTP1 may offer a promising therapeutic approach to control LUAD and improve long-term outcomes, particularly through the targeting of CSCs.