The role of homeobox genes in signaling pathway positive feedback loops and cancer therapy.

In this Perspective, the interaction between receptor components of signaling pathways and downstream transcription factors, particularly homeobox genes, is examined. The manuscript proposes that positive-feedback loops between pathway receptor components and downstream transcription factors represent a central organizing principle in development, normal cellular function, and tumor plasticity. This aspect of signaling pathway function is often overlooked, and its implications for cancer progression and therapy remain insufficiently explored. Various possible forms of this mechanism are presented. The biological logic behind this mechanism is discussed. Several prominent examples of its operation are suggested, particularly in relation to receptor tyrosine kinase (RTK)-RAS-related signaling pathways and their homeobox gene outputs in both normal and cancer states. Special attention is devoted to epithelial-mesenchymal transition (EMT), a process central to many cancers. Based on this concept, the manuscript briefly outlines the potential use of RTK- or RAS-targeted inhibitors together with epigenetic drugs in cancer therapy, with the goal of simultaneously blocking both the input and the transcriptional output of mutation-activated signaling pathways.