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000301485 041__ $$aEnglish
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000301485 1001_ $$aVarol, Ayşegül$$b0
000301485 245__ $$aComprehensive Transcriptomic Analysis in Wild-type and ATM Knockout Lung Cancer Cells: Influence of Cisplatin on Oxidative Stress-Induced Senescence.
000301485 260__ $$aAmsterdam [u.a.]$$bElsevier Science$$c2025
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000301485 500__ $$aVolume 418, 5 September 2025, 111563
000301485 520__ $$aGenetic mutations and impaired DNA repair mechanisms in cancer not only facilitate tumor progression but also reduce the effectiveness of chemotherapeutic agents, particularly cisplatin. Combination therapy has emerged as a promising strategy to overcome resistance. Comprehensive transcriptomic analyses, supported by integrated comparative bioinformatics and experimental approaches, are essential for identifying biomarkers and novel therapeutic targets underlying drug resistance. In this study, we performed overall survival and mutation analyses, examining 23 double-strand break repair proteins across more than 7,500 tumors spanning 23 distinct cancer types. Our findings identify ATM (ataxia-telangiectasia mutated) as a key protein with the highest mutation frequency. Using CRISPR/Cas9, we investigated the effects of ATM mutations on signalling pathways that influence the cellular response to cisplatin. ATM knockout enhanced cisplatin cytotoxicity by activating alternative cell death pathways, including oxidative stress-induced senescence and necroptosis. Microarray analysis revealed a regulatory interplay between ATM and NRF2 in the activation of oxidative stress-induced senescence. Specifically, ATM knockoutpromoted senescence by increasing reactive oxygen species (ROS) accumulation and downregulating NRF2 expression. To enhance combination therapy, integrating genetic profiling with advanced tools such as CRISPR/Cas9 to target oxidative stress-induced senescence may provide innovative strategies to overcome drug resistance, thereby advancing personalized cancer treatment. These approaches lay the foundation for the development of personalized cancer therapies tailored to the unique mutational landscape of individual patients, offering promising prospects for improving treatment outcomes.
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000301485 650_7 $$2Other$$aChemotherapy resistance
000301485 650_7 $$2Other$$aPersonalized cancer therapy
000301485 650_7 $$2Other$$aPrognostic biomarkers Signal transduction
000301485 650_7 $$2Other$$aSurvival analysis
000301485 650_7 $$2Other$$aTranscriptomics
000301485 7001_ $$0P:(DE-He78)514f8ac681adb9f76d5de4b07ccd143b$$aKlauck, Sabine M$$b1$$udkfz
000301485 7001_ $$aLees-Miller, Susan P$$b2
000301485 7001_ $$aEfferth, Thomas$$b3
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