Kreidberg hopes these discoveries, if replicated in adult mice, will lead to clinical testing of c-Met inhibitors in patients with PKD. He suggests that these drugs could potentially be combined with mTOR inhibitors, as well as drugs targeting other PKD pathways under study.  

"PKD is quite complex, with several regulatory pathways involved, and multiple places to target with therapy," he says.  "It will likely benefit from sub-toxic doses of multiple agents, similar to cancer chemotherapy."

c-Met inhibitors are more specific and limited in their action than mTOR inhibitors, so may be less toxic, Kreidberg adds. "There are many ongoing cancer trials with c-Met inhibitors, so there's going be increasing information on their safety and pharmacology that might help us translate this to a treatment for PKD."

Aside from its role in cancer, c-Met is essential for embryonic development and wound healing. Normally, after it's been activated, it is tagged for degradation. But Kreidberg and colleagues show that in PKD, c-Met is never tagged, because the molecule that does the tagging get trapped inside a structure in the cell known as the Golgi apparatus.

The findings are consistent with the observation of excess amounts of c-Met in the cells lining the kidney cysts of PKD patients. "c-Met is probably part of a development pathway that's turned on again, sometime in early or mid-adulthood," says Kreidberg.

Polycystic kidney disease, the fourth leading cause of kidney failure, affects more than 700,000 people in the U.S., far surpassing other genetic disorders such as cystic fibrosis and sickle-cell disease.

SOURCE Children's Hospital Boston