Enhancing sensitivity of triple‐negative breast cancer to DNA‐damaging therapy through chemical inhibition of the m6A methyltransferase METTL3

作者：Bianca Cesaro, Alessia Iaiza, F. Piscopo, Marco Tarullo, Eleonora Cesari, Dante Rotili, Antonello Mai, Alberto Diana, Michela Londero, Luca Del Giacco, Riccardo Masetti, Alba Di Leone, Chiara Naro, Silvia Masciarelli, Giulia Fontemaggi, Claudio Sette, Francesco Fazi, Alessandro Fatica · 发表于：癌症：英文版 · 年份：2023 · DOI：10.1002/cac2.12509 · 被引用次数：19 · 研究领域：RNA modifications and cancer、Cancer-related gene regulation、Epigenetics and DNA Methylation

Dear Editor, N6-methyladenosine (m6A) is a critical mRNA modification catalyzed by the enzyme methyltransferase-like 3 (METTL3), with implications in RNA metabolism. METTL3 upregulation is associated with cancer progression, metastasis, and drug resistance, making it a potential therapeutic target [1]. The small-molecule METTL3 inhibitor, STM2457, has shown promise in treating acute myeloid leukemia (AML) and has demonstrated good tolerance in mice [2, 3]. However, the specific cancer types where METTL3 inhibitors are most effective remain unknown. In breast cancer, METTL3 knockdown markedly suppresses proliferation, invasiveness, and metastasis [4]. Therefore, METTL3 inhibition is proposed as a therapeutic approach for breast cancer. Triple-negative breast cancer (TNBC), the most aggressive subtype, lacks targeted therapies, and its primary treatments involve conventional chemotherapy and DNA-damaging agents [5]. Homologous recombination deficiency, such as mutations in the breast cancer gene 1 (BRCA1) and BRCA2, serves as a predictive biomarker for identifying patients who would benefit from genotoxic chemotherapy and poly(ADP-ribose) polymerase (PARP) inhibitors. Notably, METTL3 is recruited to DNA-damaged sites and is crucial for subsequent DNA repair [6, 7]. Consequently, METTL3 knockdown reduces DNA repair activity and sensitizes cancer cells to genotoxic drugs [7, 8]. However, while TNBC exhibits elevated METTL3 levels, and its nuclear catalytic activity associates wit...