xCT inhibition sensitizes tumors to γ-radiation via glutathione reduction

// Lara Cobler 1 , Hui Zhang 1, 2 , Poojan Suri 3 , Catherine Park 1, 2 and Luika A. Timmerman 1 1 Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA 2 Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA 3 University of San Francisco, San Francisco, CA, USA Correspondence to: Luika A. Timmerman, email: Luika.Timmerman@ucsf.edu Keywords: radiation sensitize; glutathione; xCT; SLC7A11; radiation therapy Received: June 26, 2018     Accepted: July 08, 2018     Published: August 17, 2018 ABSTRACT About 3 million US cancer patients and 1.7 million EU cancer patients received multiple doses of radiation therapy (RT) in 2012, with treatment duration limited by normal adjacent tissue damage. Tumor-specific sensitization could allow treatment with lower radiation doses, reducing normal tissue damage. This is a longstanding, largely unrealized therapeutic goal. The cystine:glutamate exchanger xCT is expressed on poor prognosis subsets of most solid tumors, but not on most normal cells. xCT provides cells with environmental cystine for enhanced glutathione synthesis. Glutathione is used to control reactive oxygen species (ROS), which are therapeutic effectors of RT. We tested whether xCT inhibition would sensitize xCT + tumor cells to ionizing radiation. We found that pretreatment with the xCT inhibitor erastin potently sensitized xCT + but not xCT - cells, in vitro and in xenograft. Similarly, targeted gene inactivation also sensitized cells, and both modes of sensitization were overcome by glutathione supplementation. Sensitization prolongs DNA damage signaling, increases genome instability, and enhances cell death, revealing an unforeseen role for cysteine in genome integrity maintenance. We conclude that an xCT-specific therapeutic would provide tumor-specific sensitization to RT, allowing treatment with lower radiation doses, and producing far fewer side effects than other proposed sensitizers. Our data speaks to the need for the rapid development of such a drug.