Cancer Institute researchers have elucidated an important mechanism by which cancer cells generate the energy and raw materials needed to sustain uncontrolled growth by altering the way they metabolize glucose. The new study, published online in the journal Cell Metabolism, also reveals how glioblastoma, an aggressive brain cancer, uses this mechanism to resist targeted treatments that disrupt the Warburg effect, and suggests how such resistance might be overcome. In the process of resolving in detail the molecular pathways underlying this phenomenon, the researchers have revealed several possible new drug targets that have the potential to disrupt cancer cell metabolism to destroy tumors. Cancer and other fast-growing cells obtain energy from glucose using a process that is normally initiated only in the absence of oxygen. This allows them to accomplish the difficult task of getting the energy they need from glucose and retaining the building blocks of molecules such as lipids, proteins and DNA that are needed in large numbers to divide the cell. Until recently, little was known about the biochemical pathways that induce this important metabolic shift in cancer cells. In a study published earlier this year, Mischel and colleagues described how an aberrant growth signal, present in many glioblastomas, is transmitted to induce the Warburg effect. This signaling cascade involving the important proteins PI3 kinase (PI3K), Akt and mTORC1 ultimately activates a regulator of gene expression, the transcription factor c-Myc. Mischel said, “In many cancer cells, c-Myc appears to be the link between a lever between growth signaling pathways and the machinery that controls nutrient intake and utilization.” In the current study, a second reciprocal biochemical cascade independent of PI3K-Akt-mTORC1 signaling was identified and utilized to turn on c-Myc using a unique biochemical pathway and an unusual mechanism. mischel and colleagues report that this signaling pathway is dependent on signals from the protein complex mTORC2. The researchers demonstrated that when mTORC2 is turned on, it silences two other transcription factors, FoxO1 and FoxO3, the latter two of which inhibit c-Myc activation in the nucleus. Further, they learned that FoxOs silencing is achieved by acetylating this chemical modification. This study has important implications for cancer therapy. There are many drugs designed recently aimed at blocking PI3K-Akt-mTORC1 signaling. We confirmed that when you utilize these drugs, you will potentially drive FoxOs acetylation via mTORC2 and inadvertently drive the Warburg effect. In other words, it is possible that this new signaling pathway is responsible for tolerance to these drugs. Our data suggest that to disrupt the Warburg effect and kill cancer cells, you must develop therapies that target both signaling pathways. This is the main clinical value of the new study findings.” Glioblastomas that rely primarily on the mTORC2-mediated signaling pathway tend to have a poorer prognosis. And, their study shows that lung cancer cells also use this signaling pathway to induce the Warburg effect. We are using glioblastoma as a system to understand a variety of other cancers, and indeed, this finding has broader relevance because these signaling pathways identified are conserved across cancer cell types. Different cancers are driven by mutations in different types of growth factor receptors, and the signals transmitted by these mutant receptors tend to focus on a single set of signaling proteins.” ”We have identified important molecules associated with this signaling pathway as well as novel signaling mechanisms, opening up a landscape rich in potential new anti-cancer drug targets,” working to identify drug-like small molecules that have the potential to disrupt key steps in the mTORC2-mediated signaling pathway.