Abstract 1426: Mechanism study of METTL3/HIF-2α positive feedback loop promoting multidrug resistance in anaplastic thyroid carcinoma

Abstract Research Background: Anaplastic Thyroid Carcinoma (ATC) is an extremely lethal malignant tumor, with patients having an average survival period of typically less than five months. For ATC patients, conventional treatment methods such as surgery and radioactive iodine therapy are not effective. To date, there is no widely recognized standard treatment protocol, which has resulted in no significant improvement in patient survival rates over the past several decades. In clinical treatment, chemotherapeutic drugs doxorubicin and cisplatin are the primary treatment methods. Additionally, research shows that the multi-targeted tyrosine kinase inhibitor lenvatinib is effective for some ATC patients. However, the reality is that many patients exhibit resistance to these drugs from the early stages of treatment, greatly limiting their potential to benefit from the therapy. Research Results: Our previous research data found that compared to differentiated thyroid cells and normal thyroid cancer cells, ATC cells have a higher degree of hypoxia, and ATC patients with high tissue hypoxia scores have a worse prognosis compared to those with low hypoxia scores; in vitro experiments demonstrated that hypoxic conditions can induce ATC cell resistance to cisplatin, doxorubicin, and lenvatinib. By comparing tissues with high and low hypoxia scores, we discovered significant enrichment of ABC transport proteins. In ATC tissues, hypoxia scores were significantly negatively correlated with METTL3 expression. Under hypoxic conditions, METTL3 in ATC cells downregulates HIF-2α, thereby reducing ABC transport protein expression. We further found that METTL3 catalyzes m6A methylation modification on HIF-2α RNA, and the "reading protein" YTHDF2 recognizes this modification and participates in RNA degradation, thus reducing HIF-2α RNA levels. Interestingly, we also discovered that HIF-2α can downregulate METTL3 expression through the histone demethylase KDM2B, which removes methylation marks from the 4th lysine of histone H3, thereby suppressing downstream gene transcription. Research Conclusion: In ATC cells, the hypoxic microenvironment upregulates KDM2B through the HIF-2α pathway. KDM2B downregulates METTL3 through its demethylation action, and METTL3 performs m6A methylation modification on HIF-2α RNA, which is then recognized by YTHDF2, ultimately downregulating HIF-2α expression. This positive feedback loop significantly upregulates the expression of ABC transport proteins involved in multidrug resistance, leading to resistance to drugs such as cisplatin, doxorubicin, and lenvatinib. Citation Format: Junya Ning, Jinpu Yu. Mechanism study of METTL3/HIF-2α positive feedback loop promoting multidrug resistance in anaplastic thyroid carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1426.