Andrianov Grigorij Vasilevich

Gaponova Anna Vladislavovna

Golemis Erica

Kiyamova Ramziya Gallyamovna

Serebrijskij Ilya Genrihovich

Kazan Federal University Digital Repository

translational research1557P Identification of evolutionarily conserved DNA damageresponse (DDR) genes that alter sensitivity to cisplatinA. Gaponova1, I.G. Serebriiskii2, G. Andrianov1, R. Kiyamova1, E.A. Golemis21Biochemistry, Kazan Federal University, Kazan, Russian Federation, 2MolecularTherapeutics, Fox Chase Cancer Center, Philadelphia, PA, USABackground: Cisplatin is one of the most potent chemotherapeutic agents currently inuse for clinical treatment of many types of cancer, including head and neck cancers(HNCs) and epithelial ovarian cancers (EOCs). Like other platinum agents, it isthought to function primarily by modifying DNA, forming intrastrand crosslinks andother DNA lesions. The molecular mechanisms of resistance to cisplatin are not fullyunderstood, although some forms of resistance have been associated with changes inDNA Damage Response (DDR). Identification of the new therapeutic targets wouldboth allow a better understanding of drug resistance mechanisms, and potentiallyprovide new avenues for disease management.Methods:We have integrated data from a large number of functional screensperformed in lower eukaryotes for genes conferring resistance to cisplatin and otherDNA damaging agents such as g-ray-, X-ray-, and UV-radiation. We subsequentlyidentified human orthologues of evolutionary conserved genes that are potentiallyinvolved in DDR and cisplatin sensitivity in humans. We then directly tested the role ofsome of these genes in response to the exposure to the DNA damaging agents in EOCand HNC cell lines. We used small interfering RNAs (siRNAs) to deplete either controlgenes or candidate genes of interest, and under basal and drug-treatment conditions,we assessed cell viability,the impact on phospho-H2AX focus formation, and activationof the ATR DDR kinase. Besides cisplatin, we assessed gene effect on two additionalDNA damaging drugs, 5-fluorouracil and olaparib.Results:We identified in silico a set of candidate human genes with yeast orthologsthat are implicated in DDR and regulation of cisplatin sensitivity in Saccharomycescerevisiae, developing a novel genomic resource. Depletion of a set of empirically testedgenes sensitized human cancer cells to cisplatin and other DNA damaging drugs, andaffected phospho-H2AX foci and DDR signaling.Conclusions: Our findings suggest that possible mechanism of sensitization tocisplatin caused by depletion of these genes involves reduced activation of DDRresponses, and identifies new, non-canonical candidate regulators of DDR based onevolutionary analysis.Legal entity responsible for the study: Kazan Federal UniversityFunding: This study was supported by Russian Science Foundation (project 15–15–20032)Disclosure: All authors have declared no conflicts of interest.© European Society for Medical Oncology 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology.All rights reserved. For permissions, please email: journals.permissions@oup.com.Annals of Oncology 27 (Supplement 6): vi526–vi544, 2016doi:10.1093/annonc/mdw392.38abstracts at Kazan Federal University on October 21, 2016http://annonc.oxfordjournals.org/Downloaded from 

dentification of evolutionarily conserved DNA damage response (DDR) genes that alter sensitivity to cisplatin

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dentification of evolutionarily conserved DNA damage response (DDR) genes that alter sensitivity to cisplatin

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