title: Dual targeting of PI3K and MEK enhances the radiation response of K-RAS mutated non-small cell lung cancer.
abstract: Despite the significant contribution of radiotherapy to non-small lung cancer (NSCLC), radioresistance still occurs. One of the major radioresistance mechanisms is the hyperactivation of the PI3K/Akt pathway in which Akt facilitates the repair of DNA double-strand breaks (DSBs) through the stimulation of DNA-PKcs. We investigated if targeting PI3K would be a potential approach for enhancing the radiosensitivity of K-RAS mutated (K-RASmut) NSCLC cell lines A549 and H460. Short-term (1-2 h) pre-treatment of cells with the PI3K inhibitor PI-103 (1 μM) inhibited Akt/DNA-PKcs activity, blocked DSBs repair and induced radiosensitivity, while long-term (24 h) pre-treatment did not. Lack of an effect after 24 h of PI-103 pre-treatment was due to reactivation of K-Ras/MEK/ERK-dependent Akt. However, long-term treatment with the combination of PI-103 and MEK inhibitor PD98059 completely blocked reactivation of Akt and impaired DSBs repair through non-homologous end joining (NHEJ) leading to radiosensitization. The effect of PI3K inhibition on Akt signaling was also tested in A549 mouse xenografts. P-Akt and P-DNA-PKcs were inhibited 30 min post-irradiation in xenografts, which were pretreated by PI-103 30 min before irradiation. However, Akt was reactivated 30 min post-irradiation in tumors, which were pre-treated for 3 h with PI-103 before irradiation. After a 24 h pretreatment with PI-103, a significant reactivation of Akt was achieved 24 h after irradiation. Thus, due to MEK/ERK-dependent reactivation of Akt, targeting PI3K alone is not a suitable approach for radiosensitizing K-RASmut NSCLC cells, indicating that dual targeting of PI3K and MEK is an efficient approach to improve radiotherapy outcome.
authors.affiliation: Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, University of Tuebingen, Tuebingen, Germany.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Toulany
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Wisconsin Institute for Medical Research, Madison, WI, USA.
authors.forename: Mari
authors.initials: M
authors.lastname: Iida
authors.affiliation: Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, University of Tuebingen, Tuebingen, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Keinath
authors.affiliation: Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, University of Tuebingen, Tuebingen, Germany.
authors.forename: Firdevs F
authors.initials: FF
authors.lastname: Iyi
authors.affiliation: Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, University of Tuebingen, Tuebingen, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Mueck
authors.affiliation: Department of Dermatology, University of Tuebingen, Tuebingen, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Fehrenbacher
authors.affiliation: Tumor Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt.|Laboratory of Radiobiology and Experimental Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Wael Y
authors.initials: WY
authors.lastname: Mansour
authors.affiliation: Department of Dermatology, University of Tuebingen, Tuebingen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schaller
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Wisconsin Institute for Medical Research, Madison, WI, USA.
authors.forename: Deric L
authors.initials: DL
authors.lastname: Wheeler
authors.affiliation: Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, University of Tuebingen, Tuebingen, Germany.
authors.forename: H Peter
authors.initials: HP
authors.lastname: Rodemann
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D011836:Radiation Tolerance / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C117307:KRAS protein, human; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011838:Radiation-Sensitizing Agents; D020930:MAP Kinase Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras)
keywords: MAPK/ERK; NSCLC; PI3K/Akt; double-strand breaks; radiotherapy