rmacologic Inactivation of Kinase Suppressor of Ras1 sitizes Epidermal Growth Factor Receptor and Oncogenic Ther -Dependent Tumors to Ionizing Radiation Treatment

ownload ctive enhancement of tumor response to radiation therapy is a highly attractive objective, but it has not et clinically. Gain-of-function Ras (gf) signaling via hyperactivation of receptor tyrosine kinases, such epidermal growth factor receptor (EGFR), or via oncogenic mutation of Ras is shown to confer radionce and requires the engagement of the Raf/MEK/ERK pathway. However, upstream mediators of nteraction in cancer cells that could be targeted for radiosensitization have not been identified and chared. Here, we provide original observations both in vitro and in vivo that kinase suppressor of Ras1 ) is a new target for reversing gf Ras-mediated radioresistance. We employed EGFR-dependent A431 ous cell carcinoma (SCC) and genetically defined the molecular function of KSR1 in irradiationd Raf/MEK/ERK activation. In vitro KSR1 inactivation via genetic inhibition of its expression or kinase n abrogated ionizing radiation–induced activation of the Raf/MEK/ERK2 cascade, enhanced the cyeffect of radiation, and achieved radiosensitization associated with inhibition of DNA damage repair hancement of clonogenic death. In vivo pharmacologic inactivation of KSR1 by KSR1 AS-ODN infusion to radiosensitization in EGFR-dependent A431 SCC and in oncogenic K-Ras-driven A549 human non– cell lung carcinoma. These observations collectively establish KSR1 as a novel target iosensitization and show the feasibility of using KSR1 AS-ODN as a radiosensitizer for treating gf pendent human malignancies. Identification of such mediators of gf Ras signaling in response to irrary 22 , 2 01 6