This lecture delves into the mechanisms of sustained proliferation in cancer, focusing on the RTK/PI3K/mTOR pathway and its inhibitors like Trastuzumab, Lapatinib, and Gefitinib. It explores the activation of PI3K by p-RTK and Ras, the completed randomized trials of PI3K and AKT inhibitors in breast cancer, and the effects of Akt/PKB on survival, proliferation, and cell growth. The lecture also covers the canonical Wnt/ß-catenin signaling pathway, Familial Adenomatous Polyposis (FAP), and the role of GPCRs and G-proteins in human cancers. It concludes by discussing the progression of colorectal cancer and the additional hallmark capabilities required for its development.