Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology, and Research), Singapore 138673, Singapore.
Cells. 2024 Mar 22;13(7):564. doi: 10.3390/cells13070564.
Originally identified in in 1995, the Hippo signaling pathway plays a pivotal role in organ size control and tumor suppression by inhibiting proliferation and promoting apoptosis. Large tumor suppressors 1 and 2 (LATS1/2) directly phosphorylate the Yki orthologs YAP (yes-associated protein) and its paralog TAZ (also known as WW domain-containing transcription regulator 1 [WWTR1]), thereby inhibiting their nuclear localization and pairing with transcriptional coactivators TEAD1-4. Earnest efforts from many research laboratories have established the role of mis-regulated Hippo signaling in tumorigenesis, epithelial mesenchymal transition (EMT), oncogenic stemness, and, more recently, development of drug resistances. Hippo signaling components at the heart of oncogenic adaptations fuel the development of drug resistance in many cancers for targeted therapies including KRAS and EGFR mutants. The first U.S. food and drug administration (US FDA) approval of the imatinib tyrosine kinase inhibitor in 2001 paved the way for nearly 100 small-molecule anti-cancer drugs approved by the US FDA and the national medical products administration (NMPA). However, the low response rate and development of drug resistance have posed a major hurdle to improving the progression-free survival (PFS) and overall survival (OS) of cancer patients. Accumulating evidence has enabled scientists and clinicians to strategize the therapeutic approaches of targeting cancer cells and to navigate the development of drug resistance through the continuous monitoring of tumor evolution and oncogenic adaptations. In this review, we highlight the emerging aspects of Hippo signaling in cross-talk with other oncogenic drivers and how this information can be translated into combination therapy to target a broad range of aggressive tumors and the development of drug resistance.
最初于 1995 年在 中被鉴定出来，Hippo 信号通路通过抑制增殖和促进凋亡在控制器官大小和肿瘤抑制中发挥关键作用。大肿瘤抑制因子 1 和 2（LATS1/2）直接磷酸化 Yki 同源物 YAP（yes 相关蛋白）及其旁系同源物 TAZ（也称为 WW 结构域包含转录调节剂 1 [WWTR1]），从而抑制其核定位和与转录共激活因子 TEAD1-4 的配对。许多研究实验室的认真努力已经确立了失调的 Hippo 信号在肿瘤发生、上皮间质转化（EMT）、致癌干性中的作用，以及最近在药物耐药性的发展中的作用。Hippo 信号通路的核心成分在肿瘤适应中发挥作用，为针对 KRAS 和 EGFR 突变等靶向治疗的许多癌症的耐药性发展提供了动力。2001 年美国食品和药物管理局（US FDA）首次批准伊马替尼酪氨酸激酶抑制剂为靶向治疗铺平了道路，随后批准了近 100 种美国 FDA 和国家药品监督管理局（NMPA）批准的小分子抗癌药物。然而，低反应率和耐药性的发展对提高癌症患者的无进展生存期（PFS）和总生存期（OS）构成了重大障碍。越来越多的证据使科学家和临床医生能够制定靶向癌细胞的治疗方法，并通过持续监测肿瘤演变和致癌适应来应对耐药性的发展。在这篇综述中，我们强调了 Hippo 信号与其他致癌驱动因素相互作用的新方面，以及如何将这些信息转化为联合治疗，以靶向广泛的侵袭性肿瘤和耐药性的发展。
