Oncotarget

Research Papers:

Dual targeting of PI3K and MEK enhances the radiation response of K-RAS mutated non-small cell lung cancer

Mahmoud Toulany _, Mari Iida, Simone Keinath, Firdevs F. Iyi, Katharina Mueck, Birgit Fehrenbacher, Wael Y. Mansour, Martin Schaller, Deric L. Wheeler and H. Peter Rodemann

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Oncotarget. 2016; 7:43746-43761. https://doi.org/10.18632/oncotarget.9670

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Abstract

Mahmoud Toulany1, Mari Iida2, Simone Keinath1, Firdevs F. Iyi1, Katharina Mueck1, Birgit Fehrenbacher3, Wael Y. Mansour4,5, Martin Schaller3, Deric L. Wheeler2,*, H. Peter Rodemann1,*

1Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, University of Tuebingen, Tuebingen, Germany

2Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Wisconsin Institute for Medical Research, Madison, WI, USA

3Department of Dermatology, University of Tuebingen, Tuebingen, Germany

4Tumor Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt

5Laboratory of Radiobiology and Experimental Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

*Shared last authorship

Correspondence to:

Mahmoud Toulany, email: [email protected]

Keywords: NSCLC, PI3K/Akt, MAPK/ERK, radiotherapy, double-strand breaks

Received: January 1, 2016    Accepted: May 12, 2016    Published: May 27, 2016

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.


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