The PTEN gene controls cell growth and behavior, with its loss implicated in cancer. AstraZeneca and Babraham have collaborated to improve our understanding of how this happens.

The Babraham Institute, Cambridge, UK and AstraZeneca have unveiled research that helps us to better understand a key cancer gene, PTEN – reportedly the second most altered gene in cancers. The research, published in Molecular Cell, reveals why the loss of the gene has such a big impact in prostate and breast cancers. The group hope that these findings could boost the development of new, targeted therapies.

PTEN is a known tumour suppressor gene, meaning it keeps cell growth under control and prevents cancer. It manages this by regulating the levels of phosphatidylinositol-3,4,5-trisphosphate (PIP₃) – a molecule that activates downstream signalling components, notably protein kinase AKT, which stimulates cell growth and survival.

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But, the researchers have identified another way that PTEN prevents cancer – by controlling a similar molecule, phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2). This has been studied in human cancer cells and animal models, and the group demonstrated that the loss of PTEN leads to high levels of PI(3,4)P2, causing AKT hyperactivation. PI(3,4)P2 may also regulate other proteins involved in the spread of cancer throughout the body.

The PI3K-Akt pathway, where PTEN controls PIP₃ levels and AKT activity.

The group was surprised by the dramatic effect of losing PTEN. Project leader Phil Hawkins explained the implications of their findings on the cancer field: “We were really surprised that loss of PTEN caused such a dramatic increase in PI(3,4)P2… 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.

AstraZeneca already has an AKT inhibitor undergoing clinical trials for prostate, breast and other cancers. With an individual’s genetics playing an important part in the development of cancer, personalized approaches could prove very effective. Inbiomotion’s MAFTest identifies patients that are suitable for zoledronic acid treatment. Another approach is to block mutations key genes, as AstraZeneca has managed with its candidate, Tagrisso.

With PTEN implicated in many cancers – for example, over 40% of prostate cancers – developing a targeted approach to this mutation would be a huge step forward.


Images – Cedric Weber / shutterstock.com; ellepigrafica / shutterstock.com

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