Description:
Abstract Lung cancer remains one of the most prevalent and deadliest malignancies worldwide. Radiotherapy (RT) is a major therapeutic modality for inoperable non-small cell lung cancer (NSCLC). There is substantial evidence that ionizing radiation triggers activation of TGFβ especially in lung, breast and liver tumor. TGFβ inhibition prior to IR inhibits the DNA damage response in epithelial cells via blockade of ATM kinase activity (Cancer Res 62:5627, 2002; Cancer Res 66:10861, 2006) and sensitizes radiation responses in breast cancer cell lines and tumors (Clin Cancer Res 2011;17:6754-6765.). The current studies test whether TGFβ blockade prior to irradiation modulates radiation response of NSCLC cell lines, NCI-H1299, NCI-H292, H460 and Lewis Lung Cancer (LLC), assessed in vitro and in vivo. All NSCLC cell lines responded to TGFβ by phosphorylation of Smad2, which was blocked by LY364947, a small molecule TGFβ type 1 receptor inhibitor. NCI-H1299 and LLC were insensitive to TGFβ growth inhibition in vitro. LY364947 increased radiosensitivity in NCI-H1299 and H460 in clonogenic assays. Consistent with increased clonogenic cell death, TGFβ inhibition also compromised radiation-induced phosphorylation of H2AX and ATM in NCI-H1299. Treatment of cultured LLC cells with either small molecule TGFβ type 1 receptor inhibitor or TGFβ neutralizing antibody, 1D11, significantly increased LLC radiosensitivity as measured by clonogenic assay. Furthermore, C57BL mice bearing subcutaneous LLC tumors treated before and after RT with 1D11 or 13C4 isotype control antibody (20 mg/kg i.p.) resulted in greater tumor growth delay compared to RT and control antibody. Together, these data indicate that TGFβ inhibition prior to radiation attenuates DNA damage responses, enhances clonogenic cell killing, and promotes tumor growth delay. Given the recognized role of radiation-induced TGFβ in lung fibrosis, the therapeutic index for RT could be significantly increased if circumstances are defined in which TGFβ inhibition during RT both enhances lung cancer radiosensitivity and protects normal lung. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5715. doi:1538-7445.AM2012-5715