Glycogen Synthase Kinase-3 Beta Expression Correlates With Worse Overall Survival in Non-Small Cell Lung Cancer-A Clinicopathological Series

Marclesson Alves; Daniela de Paula Borges; Aline Kimberly; Francisco Martins Neto; Ana Claudia Oliveira; Juliana Cordeiro de Sousa; Cleto D Nogueira; Benedito A Carneiro; Fabio Tavora

doi:10.3389/fonc.2021.621050

Glycogen Synthase Kinase-3 Beta Expression Correlates With Worse Overall Survival in Non-Small Cell Lung Cancer-A Clinicopathological Series

Front Oncol. 2021 Mar 9:11:621050. doi: 10.3389/fonc.2021.621050. eCollection 2021.

Authors

Affiliations

¹ Department of Pathology, Federal University of Ceará, Fortaleza, Brazil.
² Argos Pathology Laboratory, Department of Investigative Pathology, Fortaleza, Brazil.
³ Departments of Patholoy, Oncology and Thoracic Surgery, Messejana Heart and Lung Hospital, Fortaleza, Brazil.
⁴ Division of Hematology/Oncology, Lifespan Cancer Institute, The Warren Alpert Medical School of Brown University, Providence, RI, United States.

Abstract

Background: Glycogen Synthase Kinase-3 beta (GSK-3β) regulates diverse cell functions including metabolic activity, signaling and structural proteins. GSK-3β phosphorylates target pro-oncogenes and regulates programmed cell death-ligand 1 (PD-L1). This study investigated the correlation between GSK-3β expression and clinically relevant molecular features of lung adenocarcinoma (PDL1 score, PTEN expression and driver mutations).

Methods: We evaluated 95 lung cancer specimens from biopsies and surgical resections. Immunohistochemistry was performed to analyze the expression of GSK-3β, PTEN, and PDL1. Epidemiological data, molecular characteristics and staging were evaluated from medical records. The histologic classification was performed by an experienced pulmonary pathologist.

Results: Most patients were female (52.6%) and the majority had a positive smoking history. The median age was 68.3 years, with individuals over 60 years accounting for 82.1%. The predominant histological subtype was adenocarcinoma (69.5%), followed by squamous cell carcinoma (20.0%). GSK-3β expression in tumors was cytoplasmic with a dotted pattern and perinuclear concentration, with associated membranous staining. Seven (7.3%) tumors had associated nuclear expression localization. Seventy-seven patients (81.1%) had advanced clinical-stage tumors. GSK-3β was positive in 75 tumors (78%) and GSK3-positive tumors tended to be diagnosed at advanced stages. Among stage III/IV tumors, 84% showed GSK3 positivity (p= 0.007). We identified a statistically significant association between GSK-3β and PTEN in the qualitative analysis (p 0.021); and when comparing PTEN to GSK-3β intensity 2+ (p 0.001) or 3+ expression (> 50%) - p 0.013. GSK-3β positive tumors with a high histological score had a worse overall survival.

Conclusion: We identified the histological patterns of GSK-3β expression and evaluated its potential as marker for overall survival, establishing a simple histological score to measure the evaluated status in resected tissues. The use of GSK-3β expression as an immune response biomarker remains a challenge. Future studies will seek to explain the role of its interaction with PTEN.

Keywords: glycogen synthase kinase-3 beta (GSK-3 beta); immunotherapy; lung cancer; non-small cell carcinoma; phosphatase and tensin homolog deleted on chromosome 10 (PTEN); programmed death-ligand 1 (PD-L1).