When prostate cancer meets the roadblocks set up by conventional drugs that target a hormone pathway that feeds the tumor, it often shows its craftiness by rerouting to an alternative cell signalling pathway, according to a new Cancer Cell study. The University of California Los Angeles (UCLA) researchers report a surprising discovery about the two pathways, and suggest treating both as a way to overcome the problem of hormone ablation therapy resistance which often results in cancer spreading and death.
Cancer growth relies on a combination of factors. One of these is the presence of a steady supply of “fuel”, and the other is the absence of a process that suppresses their growth. An example of the former is some form of growth hormone, and an example of the latter is the PTEN tumor suppressor gene, which normally stops cells dividing too quickly, but is mutated in cancer and stops working properly.
In the prostate, the male hormone or androgen “feeds” prostate cells as long as they can “dock” onto them, whether healthy or malignant, via their androgen receptors.
A common way to treat prostate cancer is to block the function of the androgen receptor and prevent circulating androgens from interacting with the prostate cells. But in many cases, the effect is temporary, as resistance to the treatment develops. These are known as castration resistant prostate cancers (CRPCs).
One thing we know is that in 70 to 90 percent of CRPCs, the PTEN tumor suppressor gene is inactivated, but as the authors note in their background information, quite how the loss of PTEN function is involved in the development of CRPCs has been somewhat of a mystery.
What this study reveals is that when the therapy drugs target the androgen receptors, the cancer compensates by activating another cell signalling pathway that promotes the proliferation of cancer cells with inactivated PTEN genes:
“PTEN loss suppresses androgen-responsive gene expressions by modulating androgen receptor (AR) transcription factor activity. Conditional deletion of Ar in the epithelium promotes the proliferation of Pten null cancer cells, at least in part, by downregulating the androgen-responsive gene Fkbp5 and preventing PHLPP-mediated AKT inhibition,” they write.
The compensating pathway is the PI3K/AKT/mTOR pathway.
Senior author Dr Hong Wu, a professor of molecular and medical pharmacology and a researcher at UCLA’s Jonsson Cancer Center, told the press that:
“The most significant take home message from this study is that certain prostate cancers can resist androgen deprivation therapy by activating an alternate pathway to drive its growth.”
“We found that these two pathways are talking to each other, almost like regulatory circuitry, and helping each other get around attempts to kill the cancer. When we suppress one of these pathways, it essentially feeds the other,” she added.
Wu, who also conducts research at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, said they were surprised by their discovery, as it went against conventional wisdown about how PTEN negative and PTEN positive prostate cells behave.
She explained that most theories propose that PTEN regulates how the androgen receptor pathway behaves, but their discovery suggests the opposite.
They thought when PTEN was inactivated, this activated the androgen receptor pathway, which in turn drives cancer growth. But what they found is that if cancer cells lose their PTEN function, then they become independent of androgen receptor activity and rely on the other PI3K pathway for their survival.
They went on to show that PTEN loss suppresses the ability of the androgen receptor to send signals, and this leads to the cancer cells using the other signalling pathway, which has been in constant communication with the former, for survival.
“Our findings identify PI3K and AR pathway crosstalk as a mechanism of CRPC development,” they write.
The discovery of this “crosstalk” is important, said Wu, because it addresses a key mechanism of cancer resistance. Some prostate cancers that resist hormone therapy could react unexpectedly if you then withdraw androgen treatment, because that could stimulate the PI3K pathway as an alternative driver of cancer growth.
You have to hit both pathways to check cancer growth in these types of cancer, suggests Wu.
First author Dr David J. Mulholland, a postdoctoral fellow in Wu’s lab, said these results have important implications for men with late stage prostate cancer, because this often develops resistance to hormone ablation therapy.
Resistance to therapy is the reason the disease spreads to other places, most often the bones, and dramatically reducing the chances of survival.
Mulholland said the findings reveal a mechanism that might explain why anti-androgen therapy fails in some patients. Their cancer cells find a way around the low androgen function by turning to the alternative survival route.
“It was a surprising result to show that these cells could continue to live without the androgen receptor signaling. Combining drugs that hit both pathways will be much more effective than using one drug alone,” he added.
While most of the work in the study was done in mice, the researchers also replicated the findings using samples of human prostate cancers taken from patients.
Wu said they found “similar results in both cases”.
“The human cancers may behave the same way as the mouse models,” she added.
As to the future, clinical testing of new types of androgen-receptor inhibitors that could be more effective is already under way, as are clinical trials of drugs that inhibit the PI3K pathway.
UCLA is already designing trials that will combine the two types of drug in the treatment of prostate cancer.
This year, estimates suggest more than 217,000 American men will find out they have prostate cancer, the most common cancer in men, and of those, more than 32,000 will die of it.
Funds from the National Institutes of Health, the Department of Defense, the Prostate Cancer Foundation, the California Institute for Regenerative Medicine and Jean Perkins Foundation helped to pay for the study.
David J. Mulholland, Linh M. Tran, Yunfeng Li, Houjian Cai, Ashkan Morim, Shunyou Wang, Seema Plaisier, Isla P. Garraway, Jiaoti Huang, Thomas G. Graeber, and Hong Wu.
Cancer Cell 19(6) pp. 792 – 804; 14 June 2011
DOI: 10.1016/j.ccr.2011.05.006
Additional source: University of California – Los Angeles Health Sciences.
Written by: Catharine Paddock, PhD