Mobocertinib Succinate

EGFR-TKI-resistant cell lines were established by long-term exposure to gefitinib, afatinib, and osimertinib via the PC9 model. This model helps study EGFR-TKI resistance mechanisms in non-small cell lung cancer (NSCLC) and may offer insights to improve treatment outcomes, particularly for patients unresponsive to anti-PD-1/PD-L1 therapies. We investigated molecular alterations in these resistant cell lines using multi-omics techniques, including genome sequencing, proteomics, and transcriptomics. Differential dependencies on EGFR downstream pathways were observed among resistant cell lines. Immune evasion mechanisms were analyzed to identify alterations in EGFR downstream pathways and unfolded protein response (UPR) elements contributing to immune-related transcriptional patterns. Afatinib-resistant cells exhibited the most pronounced immunosuppressive-like transcriptional features compared to gefitinib- and osimertinib-resistant cells. This was characterized by elevated PD-L1 expression, minimal changes in MHC class 1 levels, down-regulation of shared immune-modulated gene sets, and a cytokine profile favoring immunosuppression (e.g., lower IL-6, CXCL10, IFN-γ, CCL22; higher IL-8). These findings suggest a poor prognosis and limited efficacy of anti-PD-1/PD-L1 immunotherapy in NSCLC patients with similar resistance profiles. Notably, inhibition of IRE1α signaling partially reversed this immunosuppressive-like transcriptional signature, indicating a potential strategy to restore immune responsiveness in afatinib-resistant NSCLC. Our study underscores the distinct remodeling effects of different EGFR-TKIs on tumor-cell-intrinsic immunoregulatory pathways. Targeting endoplasmic reticulum (ER) stress pathways alongside immune checkpoint inhibitors may be crucial for overcoming resistance mechanisms identified here. These insights provide a rationale for personalized treatment strategies tailored to the immune-related gene-expression profiles observed in EGFR-TKI-resistant NSCLC models, aiming to enhance therapeutic responses and improve clinical outcomes.

The epidermal growth factor receptor (EGFR) mutation represents one of the most prevalent driver gene alterations in non-small cell lung cancer (NSCLC) patients. EGFR tyrosine kinase inhibitors (EGFR-TKIs), particularly third-generation agents, have emerged as the top priority for patients harboring activating mutations. This review commences with a concise introduction to the EGFR-mutated tumor microenvironment and its dynamic changes associated with EGFR-TKI administration. We systematically summarize current therapeutic options for patients who progress on EGFR-TKIs, providing an overview of immunotherapy resistance mechanisms and corresponding management strategies. Finally, this review discusses the progression patterns and subsequent therapies in patients pretreated with EGFR-TKIs who develop resistance to immunotherapy. A treatment algorithm structured around resistance typology, molecular profiling, and progression patterns provides substantial clinical value for guiding therapeutic decisions in this patient population.