Targeting Hippo signaling in cancer: novel perspectives and therapeutic potential

As highly conserved among diverse species, Hippo signaling pathway regulates various biological processes, including development, cell proliferation, stem cell function, tissue regeneration, homeostasis, and organ size. Studies in the last two decades have provided a good framework for how these fundamental functions of Hippo signaling are tightly regulated by a network with numerous intracellular and extracellular factors. The Hippo signaling pathway, when dysregulated, may lead to a wide variety of diseases, especially cancer. There is growing evidence demonstrating that dysregulated Hippo signaling is closely associated with tumorigenesis, cancer cell invasion, and migration, as well as drug resistance. Therefore, the Hippo pathway is considered an appealing therapeutic target for the treatment of cancer. Promising novel agents targeting the Hippo signaling pathway for cancers have recently emerged. These novel agents have shown antitumor activity in multiple cancer models and demonstrated therapeutic potential for cancer treatment. However, the detailed molecular basis of the Hippo signaling-driven tumor biology remains undefined. Our review summarizes current advances in understanding the mechanisms by which Hippo signaling drives tumorigenesis and confers drug resistance. We also propose strategies for future preclinical and clinical development to target this pathway.