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Aberrant expression of MRAS and HEG1 as the biomarkers for osimertinib resistance in LUAD
Mingxin Liu1, Bo Tang2, Run Xiang1,3
1Department of Thoracic Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610042, China.
Abstract:
Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are the most applied targeted therapy for EGFR-mutant lung adenocarcinoma (LUAD). The third-generation EGFR-TKI, osimertinib, is widely used throughout lung cancer treatment, with single or combination modes. One of the main barriers in osimertinib treatment is the acquired resistance and mechanisms are not fully understood. Gene expression other than genetic mutations might predict drug response and mediate resistance occurrence. We analyzed six datasets of osimertinib-resistant LUAD cells from the Gene Expression Omnibus (GEO) database and identified two hub genes, named MRAS and HEG1. We found that the expression mode of MRAS/HEG1 in LUAD was osimertinib-dependent and contributed to drug resistance. We also explored potential mechanisms of hub genes related osimertinib resistance and emphasized the M2 infiltration involved. Moreover, potential therapeutic agents conquering MRAS/HEG1-related resistance were also identified. In conclusion, MRAS and HEG1 might be responsible for osimertinib resistance and could be promising prognostic biomarkers for osimertinib response in LUAD, which might provide insights into therapeutic strategies.
Insights
Two genes, MRAS and HEG1, drive resistance to osimertinib in lung adenocarcinoma (LUAD). Targeting these genes may overcome treatment resistance and improve outcomes for LUAD patients.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are standard targeted therapy for EGFR-mutant lung adenocarcinoma (LUAD).
- Osimertinib, a third-generation EGFR-TKI, is crucial in LUAD treatment but faces acquired resistance, limiting its efficacy.
- Mechanisms underlying osimertinib resistance are not fully understood, necessitating further investigation beyond genetic mutations.
Purpose of the Study:
- To identify novel gene expression markers associated with osimertinib resistance in LUAD.
- To elucidate the role of identified genes in mediating resistance to osimertinib treatment.
- To explore potential therapeutic strategies targeting identified resistance mechanisms.
Main Methods:
- Analysis of six Gene Expression Omnibus (GEO) datasets of osimertinib-resistant LUAD cells.
- Identification of hub genes through bioinformatics analysis.
- Exploration of potential mechanisms, including M2 macrophage infiltration, related to identified hub genes.
Main Results:
- Two hub genes, MRAS and HEG1, were identified as significantly associated with osimertinib resistance in LUAD.
- The expression of MRAS and HEG1 was found to be osimertinib-dependent and contributed to acquired drug resistance.
- M2 macrophage infiltration was implicated as a potential mechanism involved in MRAS/HEG1-related osimertinib resistance.
Conclusions:
- MRAS and HEG1 are potential drivers of osimertinib resistance in LUAD.
- These genes may serve as prognostic biomarkers for predicting osimertinib response in LUAD patients.
- Targeting MRAS/HEG1 and related pathways could offer new therapeutic strategies for overcoming osimertinib resistance.
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