Toll-like receptor 4 inhibition sensitizes non-small cell lung cancer to radiotherapy.
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.
The TLR4 inhibitor, TAK242, was tested in NSCLC cell lines (murine: LLCI, KLN205; human: H1975, SW900). Cells were irradiated at 2 and 10 Gy. In vivo, KLN205 cells were implanted in DBA/2 mice and tumors were irradiated at 10Gy. Gene and protein expression of TLR4 and MyD88 were assessed in vitro and in vivo. HMGB1 secretion was quantified after RT. Clonogenic assays were performed to evaluate the effect of TAK242 on radiosensitivity in vitro. The combination of TAK242 and RT was investigated in vivo in mice bearing KLN205 tumors.
TAK242 significantly decreased NSCLC cell proliferation and migration. Radiation at 2 and 10 Gy increased TLR4 gene expression in vitro and in vivo in a dose-dependent manner. In vitro, TLR4 and HMGB1 protein expression was upregulated following radiation. TAK242 in combination with radiation enhanced radiosensitivity in vitro. 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. In vivo, the combination of RT and TAK242 significantly reduced growth of KLN205 tumors.
These findings show that TLR4 inhibition enhances RT sensitivity in NSCLC.
The TLR4 inhibitor, TAK242, was tested in NSCLC cell lines (murine: LLCI, KLN205; human: H1975, SW900). Cells were irradiated at 2 and 10 Gy. In vivo, KLN205 cells were implanted in DBA/2 mice and tumors were irradiated at 10Gy. Gene and protein expression of TLR4 and MyD88 were assessed in vitro and in vivo. HMGB1 secretion was quantified after RT. Clonogenic assays were performed to evaluate the effect of TAK242 on radiosensitivity in vitro. The combination of TAK242 and RT was investigated in vivo in mice bearing KLN205 tumors.
TAK242 significantly decreased NSCLC cell proliferation and migration. Radiation at 2 and 10 Gy increased TLR4 gene expression in vitro and in vivo in a dose-dependent manner. In vitro, TLR4 and HMGB1 protein expression was upregulated following radiation. TAK242 in combination with radiation enhanced radiosensitivity in vitro. 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. In vivo, the combination of RT and TAK242 significantly reduced growth of KLN205 tumors.
These findings show that TLR4 inhibition enhances RT sensitivity in NSCLC.
Authors
Haroun Haroun, Rutihinda Rutihinda, Diallo Diallo, Ordonez Ordonez, Nassri Nassri, Shams Shams, Pacheco Pacheco, Saidi Saidi, Bouchard Bouchard, Turgeon Turgeon, Gris Gris, Tai Tai, Oweida Oweida
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