Researchers in the Division of Tumor Cell Biology have found one way that some breast cancer cells become resistant to the targeted therapy Herceptin. Their finding helps shed light on a frustrating cancer mystery and reveals possible new drug targets for these stubborn tumor cells.
|Susan Kane and colleagues study mechanisms of drug resistance. (Photo by Markie Ramirez)|
Herceptin, also called trastuzumab, works by interacting with a protein called Her2 that is found at very high levels on the surface of some breast cancer cells. When present at high levels, Her2 sets off a chain of events that keeps the cells growing and thriving. Herceptin, on the other hand, inhibits that chain reaction and brings cancer growth to a standstill.
About one fourth of patients with breast cancer have high levels of Her2 protein, making Herceptin a strong treatment option for those patients. Herceptin can be effective in up to 70 percent of those patients, depending on the exact stage of the cancer and the other drugs that are used in combination with Herceptin.
Within one year, however, most of the cancers become resistant to Herceptin and start growing again, even if the patient is still receiving Herceptin therapy. Scientists believe that resistant breast cancer cells find another way to trigger the chain of events required for continued growth: a sort of back door to survival when the front door — Her2 — is closed.
Professor Susan E. Kane, Ph.D., and her team found that one possible key to that back door lies in a pair of related proteins, DARPP-32 and t-DARPP.
First, the researchers found that Herceptin-resistant breast cancer cells have higher levels of t-DARPP than their counterparts that respond to Herceptin. Then they looked at cells that normally respond to Herceptin and artificially increased the amount of t-DARPP in those cells. The cells with t-DARPP continued to grow in the presence of Herceptin — just like the Herceptin-resistant cells in which t-DARPP was initially observed. Researchers suspect that t-DARPP may provide cells with a way to bypass Her2 and find a different road to growth.
“It’s possible that the resistant cells are using a path that involves t-DARPP instead of Her2 to trigger downstream events required for growth and survival,” said Kane.
The team may also have found a way to block the escape route, though. When the scientists increased the amount of another, related protein called DARPP-32, the alternative path was blocked off and the cells became sensitive to Herceptin again.
“DARPP-32 definitely counteracts t-DARPP’s effect,” said Kane, “and this also gives us a clue about the alternative path that those two proteins interact with in affecting response to Herceptin.”
Although she cautioned that more work is needed to fully understand the biochemical processes involved, Kane noted that the finding could point the way toward new drug targets that may overcome Herceptin resistance. “If we can find ways to manipulate the relationship between t-DARPP and DARPP-32, we might be able to block the path that makes cells resistant,” she said.
Researchers on the study also include Long Gu, Ph.D., assistant research professor, and Sarah Waliany, a University of Southern California student whose high school work on the project helped her reach the finals in the Siemens Competition in Math, Science and Technology. The findings appeared July 13 in the online journal PLoS ONE.