Toll-like receptor 4 inhibition sensitizes non-small cell lung cancer to radiotherapy.

[UNLABELLED] Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Although radiotherapy (RT) is used to treat over half of NSCLC patients, about 30% have inherent or acquired radioresistance leading to treatment failure. There's a clinically unmet need to investigate mechanisms of radioresistance that can be targeted in combination with RT. Among these, HMGB1 has been shown to play a key role in tumor progression. Our research investigates TLR4, a receptor for HMGB1, highly expressed in NSCLC tissues, as a mediator of radioresistance.

[METHODS] The TLR4 inhibitor, TAK242, was tested in NSCLC cell lines (murine: LLCI, KLN205; human: H1975, SW900). Cells were irradiated at 2 and 10 Gy. , KLN205 cells were implanted in DBA/2 mice and tumors were irradiated at 10Gy. Gene and protein expression of TLR4 and MyD88 were assessed and . HMGB1 secretion was quantified after RT. Clonogenic assays were performed to evaluate the effect of TAK242 on radiosensitivity . The combination of TAK242 and RT was investigated in mice bearing KLN205 tumors.

[RESULTS] TAK242 significantly decreased NSCLC cell proliferation and migration. Radiation at 2 and 10 Gy increased TLR4 gene expression and in a dose-dependent manner. , TLR4 and HMGB1 protein expression was upregulated following radiation. TAK242 in combination with radiation enhanced radiosensitivity . TAK242 decreased the percentage of cells in the G1 phase, coupled with an increase in late S and G2/M, suggesting radiosensitization via cell cycle modulation. , the combination of RT and TAK242 significantly reduced growth of KLN205 tumors.

[CONCLUSION] These findings show that TLR4 inhibition enhances RT sensitivity in NSCLC.