UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, 5117 Centre Ave., Pittsburgh, PA 15213, USA; Dept. of Pathology, University of Pittsburgh School of Medicine, 5117 Centre Ave., Pittsburgh, PA 15213, USA.
UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, 5117 Centre Ave., Pittsburgh, PA 15213, USA; Dept. of Chemical Biology and Pharmacology, University of Pittsburgh School of Medicine, 5117 Centre Ave., Pittsburgh, PA 15213, USA.
Drug Resist Updat. 2023 Jul;69:100963. doi: 10.1016/j.drup.2023.100963. Epub 2023 Apr 20.
MYC is a proto-oncogene that encodes a powerful regulator of transcription and cellular programs essential for normal development, as well as the growth and survival of various types of cancer cells. MYC rearrangement and amplification is a common cause of hematologic malignancies. In epithelial cancers such as colorectal cancer, genetic alterations in MYC are rare. Activation of Wnt, ERK/MAPK, and PI3K/mTOR pathways dramatically increases Myc levels through enhanced transcription, translation, and protein stability. Elevated Myc promotes stress adaptation, metabolic reprogramming, and immune evasion to drive cancer development and therapeutic resistance through broad changes in transcriptional and translational landscapes. Despite intense interest and effort, Myc remains a difficult drug target. Deregulation of Myc and its targets has profound effects that vary depending on the type of cancer and the context. Here, we summarize recent advances in the mechanistic understanding of Myc-driven oncogenesis centered around mRNA translation and proteostress. Promising strategies and agents under development to target Myc are also discussed with a focus on colorectal cancer.
MYC 是一种原癌基因，编码转录和细胞程序的强大调节剂，这些对于正常发育以及各种类型癌细胞的生长和存活至关重要。MYC 重排和扩增是血液恶性肿瘤的常见原因。在结直肠癌等上皮性癌症中，MYC 的遗传改变很少见。Wnt、ERK/MAPK 和 PI3K/mTOR 通路的激活通过增强转录、翻译和蛋白质稳定性，显著增加 Myc 水平。升高的 Myc 通过广泛改变转录和翻译景观，促进应激适应、代谢重编程和免疫逃逸，从而推动癌症发展和治疗耐药性。尽管人们对此非常感兴趣并付出了巨大努力，但 Myc 仍然是一个难以攻克的药物靶点。Myc 和其靶标的失调具有深远的影响，具体取决于癌症的类型和背景。在这里，我们总结了围绕 mRNA 翻译和蛋白稳态的 Myc 驱动致癌作用的机制理解方面的最新进展。还讨论了针对 Myc 的有前途的开发策略和药物，重点是结直肠癌。
