Kazan medical journalKazan medical journal0368-48142587-9359Eco-Vector199910.17816/KMJ1999Research ArticleDNA repair profile in gastrointestinal stromal tumors (gists) - novel perspectives for therapyBoichukS Vboichuksergei@mail.ruRamazanovB R-GalembikovaA R-GaleevO R-MustafinI G-DuensingA-Kazan State Medical University, Kazan, RussiaUniversity of Pittsburgh Cancer Institute, Pittsburgh, USA1512201495688889128032016Copyright © 2014, Boichuk S.V., Ramazanov B.R., Galembikova A.R., Galeev O.R., Mustafin I.G., Duensing A.2014Aim. To assess the expression of various types of DNA repair proteins in gastrointestinal stromal tumors (GISTs) to identify the possible defects in DNA repair pathways and therapeutic targets. Methods. The study was performed on the human fibroblasts, imatinib-sensitive vs imatinib-resistant GISTs and leiomyosarcomas (LMS) cell lines, as well. The cell lines indicated above were cultured in the corresponding culture medium supplemented with fetal bovine serum, L-glutamine and antibiotics (37 °C и 5% СО2). Protein expression level and its intracellular localization were assessed by Western blotting. Results. The reduced BRCA1 expression was observed in most of the GIST cell lines, which was associated with an up-regulation of Rad51, thereby indicating about the potential abnormalities of homologous recombination pathway in these cells. This phenomenon was typical for GISTs and was not observed in LMS cells lines. In contrast to LMS cell lines, all GIST cells showed an upregulation of O6-methylguanine DNA methyltransferase (MGMT), the key enzyme involved in alkylated DNA damage repair pathway. Most GIST cells exhibited high level of MSH6 known as a key member of mismatch repair pathway. Most notably, topoisomerases were over-expressed in all of GIST cell lines. Conclusions. We found several striking alterations in expression levels of DDR pathway enzymes in GISTs. For instance, an up-regulation of topoisomerases in all GISTs indicates that these cells might be sensitive to topoisomerase II inhibitors and could be potentially targeted therapeutically.GISTDNA damage repairchemotherapyГИСО (GIST)репарация повреждений ДНКхимиотерапия[Boichuk S., Lee D.J., Mehalek K.R. et al. An unbiased compound screen identifies unexpected drug sensitivities and novel treatment options for gastrointestinal stromal tumors (GISTs) // Cancer Res. - 2014. - Vol. 74, N 4. - P. 1200-1213.][Burgess D.J., Doles J., Zender L. et al. Topoisomerase levels determine chemotherapy response in vitro and in vivo // Proc. Nat. Acad. Sci. - 2008. - Vol. 105. - P. 9053-9058.][Demetri G.D., Reichardt P., Kang Y.-K. et al. GRID study investigators, efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial // Lancet. - 2013. - Vol. 381. - P. 295-302.][Demetri G.D., von Mehren M., Blanke C.D. et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors // N. Engl. J. Med. - 2002. - Vol. 347. - P. 472-480.][Gramza A.W., Corless C.L., Heinrich M.C. Resistance to tyrosine kinase inhibitors in gastrointestinal stromal tumors // Clin. Cancer Res. - 2009. - Vol. 15. - P. 7510-7518.][Hirota S., Isozaki K., Moriyama Y. et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors // Science. - 1998. - Vol. 279. - P. 577-580.][Kellner U., Sehested M., Jensen P.B. et al. Culprit and victim - DNA topoisomerase II // Lancet Oncol. - 2002. - Vol. 3. - P. 235-243.][Maurel J., Martins A.S., Poveda A. et al. Imatinib plus low-dose doxorubicin in patients with advanced gastrointestinal stromal tumors refractory to high-dose imatinib // Cancer. - 2010. - Vol. 116. - P. 3692-3701.][Rock E.P., Goodman V., Jiang J.X. et al. Food and Drug Administration drug approval summary: Sunitinib malate for the treatment of gastrointestinal stromal tumor and advanced renal cell carcinoma // Oncologist. - 2007. - Vol. 12. - P. 107-113.][Rubin B.P., Singer S., Tsao C. et al. KIT activation is a ubiquitous feature of gastrointestinal stromal tumors // Cancer Res. - 2001. - Vol. 61. - P. 8118-8121.][Verweij J., Casali P.G., Zalcberg J. et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial // Lancet. - 2004. - Vol. 364. - P. 1127-1134.]