Why Some Tumors Don't Respond to Radiation and Chemotherapy

A tightly controlled system of checks and balances ensures that a powerful tumor suppressor called p53 keeps a tight lid on unchecked cell growth but doesn’t wreak havoc in healthy cells. In their latest study, scientists at the Salk Institute for Biological Studies suggest just how finely tuned the system is and how little it takes to tip the balance.

When unprovoked, at least two negative regulators—the related proteins Mdm2 and Mdmx—prevent p53 from unleashing its power to kill. But just slightly increasing the amount of available Mdmx, which grips p53 and renders it inactive, the Salk researchers discovered, made mice remarkably resistant to the harmful effects of radiation but very susceptible to the development of oncogene-induced lymphomas.

“Our experiments emphasize how subtle and precarious the balance is,” says postdoctoral researcher and first author Yunyuan V. Wang. “A slight shift of balance and the mice survive the equivalent of Chernobyl but are in big trouble when an oncogene is activated.”

Their findings, to be published in the July issue of the journal Cancer Cell, could explain why some tumors don’t respond to radiation or chemotherapy, and provide novel routes for the development of new anti-cancer therapies.

As a powerful tumor suppressor, p53 turns on genes that either halt cell division to allow time for repair of damaged DNA or, when all rescue attempts prove futile, to prevent cells with genetic defects from dividing, as this would fuel the development of cancer. Consequently, before any tumor cell can start proliferating willfully, it needs to escape from p53’s iron fist.

“One way or another, p53 function is compromised in all cancers. Either p53 itself is mutated or there is a problem with one of the proteins that regulate p53’s activity,” says the study’s leader Geoffrey M. Wahl, Ph.D., a professor in the Gene Expression Laboratory. “Our hope is that we can develop small molecule drugs that will activate p53 in those tumors where it is still functional but inactivated by one of its negative regulators.”

In an earlier study, Wahl and his team discovered that Mdm2 and Mdmx cooperate to prevent p53 from being activated, with Mdm2 being primarily responsible for degrading p53, while Mdmx is more effective at preventing p53 from turning on genes. But how p53 shakes off its negative regulators when cells experience one of the myriad stresses that activate p53 has been the topic of much discussion.

One view holds that after DNA damage occurs, enzymes directly modify p53 and that those modifications change the structure of p53 in such a way that neither Mdm2 nor Mdmx are able to bind. In an alternative scenario the same enzymes—kinases that attach phosphate groups to proteins—modify the negative regulators, accelerating their degradation and freeing p53 of their antagonists. Of course, it may well be that both views are correct, but the extent to which each contributes to p53 control remains an important unanswered question.