ArticleJournal of translational medicine2026
Inhibition of ATM reverses radioiodine resistance in differentiated thyroid cancer via genotoxic stress amplification.
Article in Journal of translational medicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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1 citing paper in PubMed.
- Cell-state transitions and microenvironmental remodeling in thyroid cancer progression revealed by single-cell and spatial transcriptomics.Frontiers in immunology · 2026Review
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10 authors.
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Abstract
backgroundRadioiodine (RAI) resistance is a major barrier in the treatment of differentiated thyroid cancer (DTC), especially in tumors that retain iodine uptake but fail to respond. The role of DNA repair mechanisms, particularly ataxia-telangiectasia mutated (ATM) kinase, in this resistance remains unclear.
methodsSingle-cell RNA sequencing (scRNA-seq) was performed on 28 thyroid cancer (TC)/adjacent normal tissues to trace ATM expression during tumor dedifferentiation using publicly available datasets. Tissue microarrays from 89 TC/adjacent normal tissues cases, including RAI-avid and RAI-refractory (RAIR) tumors, validated ATM expression patterns. Therapeutic synergy between the ATM inhibitor AZD1390 and RAI was evaluated in xenograft models and K1 thyroid cancer cells. Mechanistic studies included RNA sequencing, comet assays, cell cycle profiling, and apurinic/apyrimidinic (AP) site quantification.
resultsscRNA-seq revealed stepwise ATM upregulation during TC progression, accompanied by cell cycle dysregulation. TMA analysis confirmed significantly higher ATM expression in anaplastic thyroid cancer and RAIR tumors (median score: 21.82 vs. 4.85 in RAI-sensitive; P < 0.0001). AZD1390 combined with RAI significantly suppressed tumor growth and enhanced apoptosis (P < 0.001). Mechanistically, radioiodine exposure was associated with prominent oxidative base damage-related DNA lesions, including AP sites, whereas canonical markers of extensive and persistent double-strand break accumulation were not prominently detected under these experimental conditions. ATM inhibition did not markedly increase the initial burden of radioiodine-induced DNA lesions but impaired cell cycle checkpoint control, promoting the conversion of sublethal AP site-associated damage into lethal genomic instability.
conclusionATM promotes RAI resistance by enabling repair of AP sites and enforcing cell cycle arrest. Its inhibition converts sublethal lesions into cytotoxic damage and restores RAI sensitivity, highlighting ATM as a promising therapeutic target in RAI-refractory DTC. Further studies are required to evaluate long-term safety and durability of therapeutic response.
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