Targeting SLC7A11 with sorafenib sensitizes stereotactic body radiotherapy in colorectal cancer liver metastasis

Abstract

Colorectal cancer (CRC) with hepatic metastasis is associated with poor prognosis. Stereotactic body radiotherapy (SBRT) can provide local control for unresectable hepatic metastases of patients with CRC. However, the mechanisms of responsiveness to SBRT in metastatic CRC (mCRC) remain unclear. We aimed to identify a strategy to enhance the efficacy of SBRT in patients with CRC liver metastases and its mechanisms. Transcriptomic sequencing of CRC cells exposed to SBRT revealed that SBRT inhibited SLC7A11 expression. Downregulation of SLC7A11 enhanced the sensitivity of CRC cells to SBRT via ferroptosis. SBRT diminished the ability of tumor cells to sustain oxidative stress by impeding the phosphorylation of JNK and c-Jun and the transcription of NRF2. Furthermore, sorafenib, which targets SLC7A11, exerted inhibitory effects on tumor growth when used in combination with SBRT. A phase II clinical trial confirmed that sorafenib combined with SBRT overcame the resistance of liver mCRC with high SLC7A11 expression by inducing ferroptosis. The combination of SBRT and sorafenib demonstrated favorable clinical effects and safety, making it a good option for patients with CRC liver metastasis. STATEMENT OF SIGNIFICANCE: A novel strategy using the combination of SBRT and sorafenib for the treatment of patients with CRC hepatic metastasis was investigated. This strategy overcomes the radiation therapy resistance of mCRC by inhibiting SLC7A11 expression and promoting ferroptosis.

Keywords: Colorectal cancer; Cystine/glutamate antiporter xCT; Liver metastasis; Phase II single-arm clinical trial; SBRT; Sorafenib, Ferroptosis.