Identification of Master Regulators Driving Disease Progression, Relapse, and Drug Resistance in Lung Adenocarcinoma.

Qiong Xu,Bin Liu,Hui Qin,Qiongfang Cha,Jiantao Shi,Xueling Wu

doi:10.3389/fbinf.2022.813960

Abstract

Backgrounds: Lung cancer is the leading cause of cancer related death worldwide. Current treatment strategies primarily involve surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy, determined by TNM stages, histologic types, and genetic profiles. Plenty of studies have been trying to identify robust prognostic gene expression signatures. Even for high performance signatures, they usually have few shared genes. This is not totally unexpected, since a prognostic signature is associated with patient survival and may contain no upstream regulators. Identification of master regulators driving disease progression is a vital step to understand underlying molecular mechanisms and develop new treatments. Methods: In this study, we have utilized a robust workflow to identify potential master regulators that drive poor prognosis in patients with lung adenocarcinoma. This workflow takes gene expression signatures that are associated with poor survival of early-stage lung adenocarcinoma, EGFR-TKI resistance, and responses to immune checkpoint inhibitors, respectively, and identifies recurrent master regulators from seven public gene expression datasets by a regulatory network-based approach. Results: We have found that majority of the master regulators driving poor prognosis in early stage LUAD are cell-cycle related according to Gene Ontology annotation. However, they were demonstrated experimentally to promote a spectrum of processes such as tumor cell proliferation, invasion, metastasis, and drug resistance. Master regulators predicted from EGFR-TKI resistance signature and the EMT pathway signature are largely shared, which suggests that EMT pathway functions as a hub and interact with other pathways such as hypoxia, angiogenesis, TNF-α signaling, inflammation, TNF-β signaling, Wnt, and Notch signaling pathways. Master regulators that repress immunotherapy are enriched with MYC targets, E2F targets, oxidative phosphorylation, and mTOR signaling. Conclusion: Our study uncovered possible mechanisms underlying recurrence, resistance to targeted therapy, and immunotherapy. The predicted master regulators may serve as potential therapeutic targets in patients with lung adenocarcinoma.

Highlights

Lung cancer is the leading cause of cancer-related death worldwide, and over 2.21 million new cases was reported in 2020 (Ferlay et al, 2021)
We have evaluated 29 lung adenocarcinoma signatures curated in a previous study (Supplementary Table S1) (Tang et al, 2017) and found only two pairs of signatures shared more than 10% of their genes, as measured by Jaccard index (Figure 1)
To demonstrate the effectiveness of this method, we have tested the best-scoring signature (Xie signature) (Xie et al, 2011), benchmarked in a previous review study (Tang et al, 2017). Since it is associated with overall survival, we have compared it to the embryonic stem cell (ESC) signature which is known to be associated with poor survival in multiple cancer types including lung adenocarcinoma (LUAD) (Ben-Porath et al, 2008)

Summary

Introduction

Lung cancer is the leading cause of cancer-related death worldwide, and over 2.21 million new cases was reported in 2020 (Ferlay et al, 2021). Current treatment strategies for NSCLC primarily involve surgery, chemotherapy, radiotherapy, molecularly targeted therapy, and immunotherapy, determined by TNM stages, histologic types, and genetic profiles. Surgical resection is the treatment of first choice for early-stage (stage I-II) NSCLC patients. Patients with stage I or II lung adenocarcinoma (LUAD) have 60–70% 5-year survival after surgical resection (Booth et al, 2010). For inoperable NSCLC harboring EGFR mutations, EGFR tyrosine kinase inhibitors (TKI) was received as the first-line therapy, but most patients eventually become resistant within 8–14 months (Yu et al, 2013). For inoperable NSCLC without EGFR mutation, PD-1/PD-L1 immune checkpoint inhibitor (ICI) has become the first-line therapy. Targeted therapy and immunotherapy have revolutionized the treatment landscape of NSCLC, it remains the leading cause of cancer death. Understanding the prognostic factors and underlying molecular mechanisms of NSCLC are vital steps towards new treatments

Methods

Results

Conclusion