Research Papers:

Acquired resistance to tyrosine kinase inhibitors may be linked with the decreased sensitivity to X-ray irradiation

Maxim Sorokin, Roman Kholodenko, Anna Grekhova, Maria Suntsova, Margarita Pustovalova, Natalia Vorobyeva, Irina Kholodenko, Galina Malakhova, Andrew Garazha, Artem Nedoluzhko, Raif Vasilov, Elena Poddubskaya, Olga Kovalchuk, Leila Adamyan, Vladimir Prassolov, Daria Allina, Denis Kuzmin, Kirill Ignatev, Andreyan Osipov and Anton Buzdin _

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Oncotarget. 2018; 9:5111-5124. https://doi.org/10.18632/oncotarget.23700

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Maxim Sorokin1,2,3, Roman Kholodenko3, Anna Grekhova4, Maria Suntsova1,5, Margarita Pustovalova4, Natalia Vorobyeva1,4, Irina Kholodenko6, Galina Malakhova2, Andrew Garazha1,7, Artem Nedoluzhko2, Raif Vasilov2, Elena Poddubskaya8, Olga Kovalchuk9, Leila Adamyan10, Vladimir Prassolov5, Daria Allina11, Denis Kuzmin12, Kirill Ignatev13, Andreyan Osipov1,4 and Anton Buzdin2,3,5,7

1D. Rogachev Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow 117198, Russia

2National Research Centre “Kurchatov Institute”, Centre for Convergence of Nano-, Bio-, Information and Cognitive Sciences and Technologies, Moscow 123182, Russia

3Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia

4State Research Center-Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency, Moscow 123098, Russia

5Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia

6Orekhovich Institute of Biomedical Chemistry, Moscow 119121, Russia

7OmicsWay Corp., Walnut, CA 91789, USA

8Clinical Center Vitamed, Moscow 121309, Russia

9Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K3M4, Canada

10Department of Reproductive Medicine and Surgery, Moscow State University of Medicine and Dentistry, Moscow 127206, Russia

11Pathology Department, Morozov Children’s City Hospital, Moscow 119049, Russia

12LLC “Solixant”, Moscow 119991, Russia

13Republic Oncological Hospital, Petrozavodsk 185000, Russia

Correspondence to:

Anton Buzdin, email: [email protected]

Keywords: tyrosine kinase; serine and threonine kinase; X-ray irradiation; drug resistance; DNA repair

Received: June 05, 2017    Accepted: December 11, 2017    Published: December 27, 2017


Acquired resistance to chemotherapy and radiation therapy is one of the major obstacles decreasing efficiency of treatment of the oncologic diseases. In this study, on the two cell lines (ovarian carcinoma SKOV-3 and neuroblastoma NGP-127), we modeled acquired resistance to five target anticancer drugs. The cells were grown on gradually increasing concentrations of the clinically relevant tyrosine kinase inhibitors (TKIs) Sorafenib, Pazopanib and Sunitinib, and rapalogs Everolimus and Temsirolimus, for 20 weeks. After 20 weeks of culturing, the half-inhibitory concentrations (IC50) increased by 25 – 186% for the particular combinations of the drugs and cell types. We next subjected cells to 10 Gy irradiation, a dose frequently used in clinical radiation therapy. For the SKOV-3, but not NGP-127 cells, for the TKIs Sorafenib, Pazopanib and Sunitinib, we noticed statistically significant increase in capacity to repair radiation-induced DNA double strand breaks compared to naïve control cells not previously treated with TKIs. These peculiarities were linked with the increased activation of ATM DNA repair pathway in the TKI-treated SKOV-3, but not NGP-127 cells. Our results provide a new cell culture model for studying anti-cancer therapy efficiency and evidence that there may be a tissue-specific radioresistance emerging as a side effect of treatment with TKIs.

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