Pharmacologic inactivation of kinase suppressor of Ras1 sensitizes epidermal growth factor receptor and oncogenic Ras-dependent tumors to ionizing radiation treatment.
Selective enhancement of tumor response to radiation therapy is a highly attractive objective, but it has not been met clinically. Gain-of-function Ras (gf) signaling via hyperactivation of receptor tyrosine kinases, such as the epidermal growth factor receptor (EGFR), or via oncogenic mutation of Ras is shown to confer radioresistance and requires the engagement of the Raf/MEK/ERK pathway. However, upstream mediators of such interaction in cancer cells that could be targeted for radiosensitization have not been identified and characterized. Here, we provide original observations both in vitro and in vivo that kinase suppressor of Ras1 (KSR1) is a new target for reversing gf Ras-mediated radioresistance. We employed EGFR-dependent A431 squamous cell carcinoma (SCC) and genetically defined the molecular function of KSR1 in irradiation-induced Raf/MEK/ERK activation. In vitro KSR1 inactivation via genetic inhibition of its expression or kinase function abrogated ionizing radiation-induced activation of the Raf/MEK/ERK2 cascade, enhanced the cytotoxic effect of radiation, and achieved radiosensitization associated with inhibition of DNA damage repair and enhancement of clonogenic death. In vivo pharmacologic inactivation of KSR1 by KSR1 AS-ODN infusion leads to radiosensitization in EGFR-dependent A431 SCC and in oncogenic K-Ras-driven A549 human non-small cell lung carcinoma. These observations collectively establish KSR1 as a novel target for radiosensitization and show the feasibility of using KSR1 AS-ODN as a radiosensitizer for treating gf Ras-dependent human malignancies. Identification of such mediators of gf Ras signaling in response to irradiation holds promises for improving the therapeutic efficacy of radiation therapy and our ability to eradicate tumor.
Xiao
Hongyan
H
Departments of Pathology, Radiation and Cellular Oncology, The University of Chicago, Chicago, Illinois 60637, USA.
Zhang
Qingbei
Q
Shen
Jikun
J
Bindokas
Vytas
V
Xing
H Rosie
HR
D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D015689:Oncogene Protein p21(ras) / Q000378:metabolism*; D011494:Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D011839:Radiation, Ionizing; D015398:Signal Transduction
D011494:Protein Kinases; C097199:KSR-1 protein kinase; D066246:ErbB Receptors; D015689:Oncogene Protein p21(ras)