An innovative study has uncovered two genes that promote the formation of prostate tumours. Both genes activate a signalling pathway that plays a part in the growth, division and death of cells and is therefore important for regulating the cell cycle.
Previous research has shown that this pathway, called the PI3K-AKT pathway, is frequently mutated in prostate cancer. Although the most common mutation, in a gene called Pten, had already been identified before this new study, scientists had not assessed the possible contributions of other genetic alterations.
Now, newly identified disease-causing genes, known as Bzw2 and Eif5a2, have been shown to cooperate with this common mutation, speeding the development of prostate cancer.
A deeper understanding of the genetics behind prostate cancer, which claims thousands of lives every year in the UK alone, could open the door to new treatment approaches that could vastly improve outcomes for people living with the disease.
The study, which has been published in the Nature journal Oncogene, was led by scientists at The Institute of Cancer Research, London, and funded by Prostate Cancer UK.
Taking a novel approach to screening
Multiple genetic mutations have already been associated with prostate cancer, but it has proven difficult to distinguish between those that are directly responsible for the development and progression of the disease and those that occur simultaneously but do not give the cancer cells any growth advantages.
In addition, there has been little research into how combinations of different mutations might further promote cancer progression. This study aimed to get more insight into the processes that drive early-stage prostate cancer, with the long-term goal of informing the diagnosis and treatment of the disease.
The researchers decided to focus on genes involved in the PI3K-AKT pathway because of its known link with prostate cancer. They began by searching for genes associated with precancerous lesions of the prostate, known as prostate neoplasia, which increase the risk of prostate cancer. They screened for genes in samples from mice with mutations in the tumour suppressor gene Pten. The paper notes that this gene is linked to 20 per cent of primary prostate cancers and up to 40 per cent of metastatic prostate cancer samples.
The scientists knocked out one copy of the Pten gene in the mice to predispose them to cancer. However, they did not alter the second copy because they wanted to determine which other genes might be cooperating with the low Pten expression to promote cancer progression.
They then used a technique called transposon mutagenesis screening to assess gene activity. This process uses an enzyme to ‘cut and paste’ sections of DNA between different parts of the genome, helping reveal specific genetic mechanisms. Based on their findings, the researchers chose to follow up the Bzw2 and Eif5a2 genes.
In the second stage of the study, the researchers used prostate organoid models – mini versions of the prostate created in the lab – to further assess these genes. They found that alterations to both genes activated the PI3K-AKT pathway and promoted growth of the cancer. In addition, organoids with high Eif5a2 expression were shown to be sensitive to AKT inhibitors.
As a final step, the team analysed two databases of human prostate cancer samples, which confirmed a correlation between increased Eif5a2 expression and activation of the PI3K-AKT pathway in people.
Additional evidence supporting AKT inhibitors
Previous research has confirmed that loss-of-function mutations affecting the Pten gene result in the activation of a type of enzyme called AKT. Active AKT can limit the processes that lead to the death of cancer cells, thereby prolonging their survival, and it can promote the growth of cells.
AKT inhibitors have been shown to stop tumour cells from growing and dividing, and several ongoing trials are exploring their use in combination with other treatments.
These treatments are still relatively new in cancer; it was only at the end of 2023 that the Food and Drug Administration (FDA) approved the first one – Truqap (capivasertib) – for the treatment of breast cancer in the United States. The Institute of Cancer Research (ICR) had a pivotal role in the discovery and development of capivasertib, which is still under review as a treatment for prostate cancer.
This new study provides further evidence to support the effectiveness of these drugs for people with prostate cancer, showing that Eif5a2 is more highly expressed in prostate cancer cells and that these cells are responsive to treatment with AKT inhibitors.
Providing new hope
First author Dr Jeff Francis, Senior Scientific Officer in the Development and Cancer Group in the Division of Cancer Biology at the ICR, said:
“This study gave us the chance to investigate the early stage of prostate cancer, which has been somewhat overlooked in the research.
“Eif5a2 has been implicated in previous studies focusing on different types of cancer, suggesting that its involvement could be a common theme in oncology. As a result, we hope that this work will be useful for the cancer research community more broadly.”
Senior author Dr Amanda Swain, Group Leader in the Division of Cancer Biology at the ICR, said:
“This work suggests that there are many ways to activate the PI3K pathway in prostate cancer, and we are pleased to have validated two more genes that have a key role. We have also confirmed that Eif5a2 is amplified in people with prostate cancer and that high levels of this gene make the cancerous cells sensitive to AKT inhibitors. This provides new hope for the future of treatment with AKT inhibitors.
“Further down the line, we might be able to use Eif5a2 expression as a marker to determine which patients are most likely to respond to drugs such as capivasertib. This could optimise treatment decision-making and ultimately lead to better outcomes for people with prostate cancer.”
This is just the beginning
Hayley Luxton, Senior Research Impact & Intelligence Manager at Prostate Cancer UK, said:
“Prostate cancer is the most common cancer in men and the second largest cause of cancer death worldwide, but there’s so much more we need to understand about the genes that accelerate the growth and spread of the disease.
“We’re extremely pleased to have funded this work, which provides valuable new insight into the role of two particular genes in driving prostate cancer development and progression. By investigating these genes and their pathways, we can apply potential drug targets that could be harnessed with novel treatments. And with this knowledge we can help to identify those patients who are most likely to respond to these treatments.
“There is still so much we need to learn about prostate cancer, and we eagerly look forward to seeing how this work progresses over the coming years.”