Discovered: How Advanced Cancer Cells Outwit Hormonal Therapy

Hormonal therapy can be effective for many years in controlling advanced prostate cancer. But it does not keep cancer in check forever. One reason is that as the cancer grows and changes, it develops cells that become resistant to male hormones, also called androgens. Hormone-resistant, also called "castration resistant," cancers are very difficult to kill. 

Now, scientist Jun Luo, Ph.D., has discovered a major secret to advanced cancer’s evolution: The androgen receptor – a genetic lock, for which androgens are the key – is rendered useless. Imagine a key, perfectly suited for a particular lock – and suddenly, the keyhole is missing. 

In exciting work published in the journal, Cancer Research, Luo and colleagues have discovered that some advanced cancer genes splice, and when they do, they shed the androgen receptor binding site – creating cancer cells that cannot be affected by hormones, because they no longer speak that language. There is no lock for the key. In other words, some advanced cancer cells evolve in such a way that they’re one step ahead of the drugs designed to kill them. "New drugs developed for the treatment of castration-resistant prostate cancer, such as abiraterone, are designed to suppress signaling of the androgen receptor," says Luo. "Specifically, these drugs target one particular area of the androgen receptor called the ligand-binding domain. But when these variant cells evolve, they don’t have that particular domain." Because these streamlined cancer cells don’t have the intended target of the drugs designed to kill them, they are suddenly "drug-resistant." 

Luo and colleagues have discovered 
that some advanced cancer genes splice, 
and when they do, 
they shed the androgen receptor binding site 
– creating cancer cells that 
cannot be affected by hormones, 
because they no longer speak that language.

"Indeed," says Luo, "as prostate cancer cells adapt to these drugs, they shift to produce more of these variant cells, and their whole mechanism of sustaining cell growth changes, as well." These rapidly adapting prostate tumor cells escape hormonal therapy unscathed. "What we hope to do next is to learn how frequently and how quickly this molecular shift occurs in men receiving hormonal therapy, and work with others to develop new ways to overcome this drug resistance."

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