TIAM2 Contributes to Osimertinib Resistance, Cell Motility, and Tumor-Associated Macrophage M2-like Polarization in...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Osimertinib therapy improves outcomes for EGFR-mutated lung adenocarcinoma (LUAD).
• Acquired resistance to osimertinib limits long-term patient benefit, occurring around one year post-treatment.
• Lipid metabolism and tumor-associated macrophages (TAMs) are implicated in drug resistance, warranting further investigation.

Purpose of the Study:

• To investigate the association between lipid metabolism and osimertinib resistance in LUAD.
• To develop and validate an osimertinib resistance index (ORi) linked to lipid metabolism.
• To identify key genes and pathways contributing to osimertinib resistance.

Main Methods:

• Construction and validation of an ORi using TCGA and GEO datasets.
• Analysis of the relationship between ORi and immune cell infiltration.
• Weighted gene co-expression network analysis to identify hub genes, focusing on the M2/M1 macrophage ratio.
• In vitro validation of the identified hub gene, TIAM2.

Main Results:

• A nine-gene ORi was successfully developed, accurately reflecting osimertinib resistance and predicting prognosis in LUAD patients.
• The ORi demonstrated a correlation with M2-like TAM infiltration.
• The gene TIAM2 was identified as a hub gene, promoting osimertinib tolerance, enhancing cell motility, and driving M2-like TAM polarization in LUAD.

Conclusions:

• Lipid metabolism genes are significantly associated with osimertinib resistance in LUAD.
• The gene TIAM2 plays a crucial role in promoting osimertinib resistance, increasing cell motility, and inducing M2-like TAM polarization.