Systems Biology & Personalised Medicine Division, Walter & Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia Faculty of Medicine, Dentistry & Health Sciences, Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia Department of Medical Oncology, Royal Melbourne Hospital, Parkville & Western Hospital, Footscray, Victoria, Australia *Author for correspondence: oliver.sieber@ludwig.edu.au Therapeutic options for treating patients with metastatic colorectal cancer (CRC) have increased markedly over the past decade. Recent improvements in overall survival rates from 10 to 24 months have been achieved through the introduction of molecularly targeted agents to complement traditional cytotoxics, including agents directed against the EGF receptor (EGFR) pathway (cetuximab and panitumumab) and angiogenesis (bevacizumab, aflibercept and regorafenib). This progress has spurred intense efforts to develop further compounds that target key molecular pathways driving carcinogenesis. One major focus has been on the inhibition of oncogenic PI3K signaling, with diverse inhibitors currently in Phase I/II clinical trials. While achieving clear responses in some cancers, activity in CRC has been modest, with disease stabilization observed in approximately 10% of patients. Here, we discuss the potential opportunities of targeting the PI3K pathway in treating patients with metastatic CRC. PI3K/AKT signaling is typically initiated via growth factors (e.g., EGF) or insulin, resulting in activation of receptor tyrosine kinases or G-protein coupled receptors. Activated receptor tyrosine kinases/G-protein coupled receptors recruit and activate class IA PI3K at the cell membrane, enabling PI3K to convert PIP2 to PIP3. PIP3 recruits the serene–threonine protein kinase AKT, which is rendered fully active through phosphorylation by PDK1 and mTORC2. Phosphorylated AKT transduces the signal to a range of downstream substrates (e.g., NF-κB, TSC1/2 complex, mTORC1, S6K, 4EBP1, BAD, GSK3β and MDM2) affecting cell proliferation, growth, survival, apoptosis, protein synthesis and glucose metabolism [1]. PI3K signaling is negatively regulated by the PTEN phosphatase, which removes the 3-phosphate from PIP3. In addition, PI3K can be stimulated by GTP-bound RAS, a crosstalk important for RAS mutation-induced transformation of mammalian cells. Michelle Palmieri1,2, Jayesh Desai1,3 & Oliver Sieber*,1