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Drug Discov Today. 2024 Nov;29(11):104189. doi: 10.1016/j.drudis.2024.104189. Epub 2024 Sep 19.
Metabolic and transcriptional reprogramming are crucial hallmarks of carcinogenesis that present exploitable vulnerabilities for the development of targeted anticancer therapies. Through controlling the balance of the cellular methionine (MET) metabolite pool, MET adenosyl transferase 2 alpha (MAT2A) regulates crucial steps during metabolism and the epigenetic control of transcription. The aberrant function of MAT2A has been shown to drive malignant transformation through metabolic addiction, transcriptional rewiring, and immune modulation of the tumor microenvironment (TME). Moreover, MAT2A sustains the survival of 5'-methylthioadenosine phosphorylase (MTAP)-deficient tumors, conferring synthetic lethality to cancers with MTAP loss, a genetic alteration that occurs in ∼15% of all cancers. Thus, the pharmacological inhibition of MAT2A is emerging as a desirable therapeutic strategy to combat tumor growth. Here, we review the latest insights into MAT2A biology, focusing on its roles in both metabolic addiction and gene expression modulation in the TME, outline the current landscape of MAT2A inhibitors, and highlight the most recent clinical developments and opportunities for MAT2A inhibition as a novel anti-tumor therapy.
代谢和转录重编程是癌症发生的关键特征，为开发靶向抗癌疗法提供了可利用的弱点。通过控制细胞蛋氨酸（MET）代谢物池的平衡，MET 腺苷转移酶 2 阿尔法（MAT2A）调节代谢和转录的表观遗传控制过程中的关键步骤。已经表明，MAT2A 的异常功能通过代谢成瘾、转录重编程以及肿瘤微环境（TME）的免疫调节来驱动恶性转化。此外，MAT2A 维持 5'-甲基硫腺苷磷酸化酶（MTAP）缺陷型肿瘤的存活，赋予 MTAP 缺失的癌症合成致死性，这种遗传改变发生在所有癌症的约 15%。因此，MAT2A 的药理学抑制正在成为一种有前途的治疗策略，以对抗肿瘤生长。在这里，我们回顾了 MAT2A 生物学的最新见解，重点介绍了它在代谢成瘾和 TME 中基因表达调节中的作用，概述了当前的 MAT2A 抑制剂景观，并强调了 MAT2A 抑制作为一种新型抗肿瘤疗法的最新临床进展和机会。
