AstraZeneca Partnered Study Shed Lights on Mysterious Cancer Gene

AstraZeneca Partnered Study Shed Lights on Mysterious Cancer Gene

The PI3K signaling pathway regulates cell growth and movement and is heavily mutated in cancer. Class, I PI3Ks synthesize the lipid messenger PI(3,4,5)P₃. PI(3,4,5)P₃ can be dephosphorylated by 3- or 5-phosphatases, the latter producing PI(3,4)P₂.

A long-running collaboration between researchers at the Babraham Institute, Cambridge and the AstraZeneca IMED Biotech Unit now reveals new insights into how the PTEN gene may control cell growth and behavior and how its loss contributes to the development and advancement of certain cancers.

“Over 40% of prostate cancers lose PTEN and some lose both PTEN and another tumor suppressor gene, INPP4B, but we didn’t previously have a clear picture of how this affects tumor growth,” says IMED Biotech Unit scientist Sabina Cosulich, at AstraZeneca. “The new discovery has given us an important link between the biochemical function of PTEN and its role in prostate cancer, and in some triple negative breast tumors for which treatment is currently limited.”

The scientists have been able to establish how PTEN tumor suppressor is thought to function primarily as a PI(3,4,5)P₃ 3-phosphatase, limiting activation of this pathway. PTEN can also reduce the levels of another similar molecule known as phosphatidylinositol-3,4-bisphosphate (PI(3,4)P₂). The role of PI(3,4)P₂ is still

becoming clear but it may be able to alter the activity of the AKT protein, a key regulator of cell growth. PI(3,4)P₂ may also influence several other proteins that regulate the process of invasion; how cancer cells spread and move through the body.

By modifying previous techniques, the Babraham Institute scientists revealed that PTEN suppresses tumor growth not through one mechanism as previously thought, but two. They showed that, within the PI3K cell signaling pathway, PTEN regulates the production of two lipid messengers. These are needed for activation of AKT – a protein that mediates cell growth and is a target for novel anti-cancer drugs.

Speaking about the research, Dr Hawkins said: “We were really surprised that loss of PTEN caused such a dramatic increase in PI(3,4)P₂ in our mouse model of prostate cancer. PI(3,4)P₂ has generally been a bit of an enigma and many thought it was just a by-product of PI(3,4,5)P₃. Our work suggests that studying PI(3,4)P₂-regulated processes may reveal why PTEN is such a powerful tumor suppressor and may also help us to identify new therapeutic targets in PTEN-mutated cancers.”

Dr Cosulich concludes: “Having such an open collaboration was essential for addressing a scientific puzzle of great significance to cancer research. Our team members are in regular contact and frequently work alongside each other. Hearing about the lipid biochemistry research from the Babraham Institute team and realising how we could translate its potential from an oncology perspective was a great moment for all of us!”