Chryseobacterium indologenes mediates resistance to osimertinib by activating the IGF1R pathway in EGFR-mutant lung adenocarcinoma

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Introduction: Lung cancers harboring sensitizing epidermal growth factor receptor (EGFR) mutations typically exhibit an initial response to osimertinib; however, the development of resistance is inevitable, and there are currently no approved targeted therapies available once resistance emerges. Accumulating evidence indicates that intra-tumoral bacteria can influence tumor biology and contribute to therapy resistance in several cancer types, including pancreatic and colorectal cancer. Despite these findings, whether intra-tumoral bacteria play a role in modulating response and resistance to osimertinib in EGFR-mutant lung adenocarcinoma remains largely unexplored. This study aims to investigate the contribution of intra-tumoral bacteria to osimertinib resistance, thereby providing new insights into resistance mechanisms and identifying potential therapeutic strategies. Methods: Bacteria previously identified in lung cancer tissue samples were cultured in liquid growth medium, and their preconditioned medium (PCM) was collected. PC9 cells were treated with PCM in the presence or absence of osimertinib to screen for bacteria capable of mediating resistance. Cell viability was assessed using Cell Counting Kit-8 assays. To investigate potential mechanisms, Western blotting and receptor tyrosine kinase (RTK) phosphorylation arrays were performed. Control groups included cells treated with osimertinib alone, PCM alone, or vehicle. Statistical analyses were conducted using Student's t-test as appropriate, with p < 0.05 considered statistically significant. Data represent mean ± SD from at least three independent experiments. Results: restored cell viability in EGFR-mutant lung adenocarcinoma cells treated with osimertinib. PCM exposure markedly increased insulin-like growth factor-1 receptor (IGF1R) phosphorylation levels. PCM did not enhance cell viability when IGF1R was silenced or inhibited with linsitinib, demonstrating the pathway's essential role. Proteinase K treatment abolished the ability of PCM to protect cells from osimertinib, and removal of proteins potentially interacting with IGF1R further diminished its efficacy. Finally, PCM also conferred resistance to osimertinib in patient-derived EGFR-mutant lung adenocarcinoma cell lines. Conclusion: may significantly influence sensitivity to osimertinib or impart resistance in EGFR-mutant lung adenocarcinoma by activating the IGF1R signaling pathway.

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