Thoracic cancer · 2026
Interleukin-1α-Mediated Activation of TNF-α/NF-κB Signaling Confers Resistance to Osimertinib in EGFR-Mutant Non-Small-Cell Lung Cancer.
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Winardi Wira, Mitsuishi Yoichiro, Matsuda Hironari, Takahashi Fumiyuki, Hayakawa Daisuke, Kanamori Koichiro, Nakamura Ikuko, Wirawan Aditya, Hidayat Moulid, Wibowo Adityo, Shukuya Takehito, Tajima Ken, Hayashi Takuo, Kohsaka Shinji, Takahashi Kazuhisa
Аннотация
BACKGROUND: Lung cancer is the leading cause of cancer-related deaths worldwide. Although osimertinib is more effective than previous-generation drugs, its efficacy is often limited by both primary and acquired resistance. Cycling cancer persister cells (CPCs) have recently emerged as a transient, drug-tolerant subpopulation that may contribute to early resistance to targeted therapies. However, their biological characteristics and role in osimertinib resistance remain poorly understood.
METHODS: We established osimertinib-resistant CPCs derived from epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) cell lines PC9 and HCC827. RNA sequencing (RNA-seq) was performed to identify CPC-specific transcriptional programs.
RESULTS: RNA-seq analyses demonstrated that the tumor necrosis factor alpha (TNF-α)/nuclear factor-κB (NF-κB) signaling pathway was upregulated in osimertinib-resistant PC9 cells (PC9-CPCs), with interleukin-1 alpha (IL-1α) being the most significantly overexpressed gene. Treatment with IL-1α increased TNF-α and NF-κB p65 expression in PC9 parental cells, whereas IL-1α inhibition decreased TNF-α expression in PC9-CPCs. Consequently, the inhibition of either IL-1α or TNF-α restored the sensitivity of EGFR-mutant NSCLC cells to osimertinib. Immunohistochemical analysis confirmed that NF-κB expression was higher in tumor specimens from patients who had developed osimertinib resistance than in specimens collected before treatment.
CONCLUSION: CPCs exhibit a distinct inflammatory phenotype driven by IL-1α-driven activation of the TNF-α/NF-κB axis, representing an alternative mechanism underlying osimertinib resistance. Targeting IL-1α or TNF-α may provide a promising strategy to overcome resistance in patients with EGFR-mutant NSCLC.
METHODS: We established osimertinib-resistant CPCs derived from epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) cell lines PC9 and HCC827. RNA sequencing (RNA-seq) was performed to identify CPC-specific transcriptional programs.
RESULTS: RNA-seq analyses demonstrated that the tumor necrosis factor alpha (TNF-α)/nuclear factor-κB (NF-κB) signaling pathway was upregulated in osimertinib-resistant PC9 cells (PC9-CPCs), with interleukin-1 alpha (IL-1α) being the most significantly overexpressed gene. Treatment with IL-1α increased TNF-α and NF-κB p65 expression in PC9 parental cells, whereas IL-1α inhibition decreased TNF-α expression in PC9-CPCs. Consequently, the inhibition of either IL-1α or TNF-α restored the sensitivity of EGFR-mutant NSCLC cells to osimertinib. Immunohistochemical analysis confirmed that NF-κB expression was higher in tumor specimens from patients who had developed osimertinib resistance than in specimens collected before treatment.
CONCLUSION: CPCs exhibit a distinct inflammatory phenotype driven by IL-1α-driven activation of the TNF-α/NF-κB axis, representing an alternative mechanism underlying osimertinib resistance. Targeting IL-1α or TNF-α may provide a promising strategy to overcome resistance in patients with EGFR-mutant NSCLC.