Scientists have found that a key protein implicated in blood cancers also is important to normal development of adult blood stem cells. The finding, published in the Aug. 11 issue of Blood, suggests that for some patients emerging anticancer drugs that target the protein may cause more harm than good.
|Ravi Bhatia is exploring factors that could help guide treatment of blood cancers. (Photo by Walter Urie)|
Researchers in the Division of Hematopoietic Stem Cell and Leukemia Research led a study to understand what role, if any, a protein called SHP2 plays in the growth and development of adult hematopoietic stem cells, the parent cells of all blood and immune system cells.
Previous research has shown that SHP2 is key to the development of blood and immune system cells in mice, particularly in the early stages of life.
Liang Li, Ph.D., staff scientist, and Ravi Bhatia, M.D., professor and division director, studied SHP2 in the hematopoietic stem cells of human adults — and found that it helps guide the development of these cells, as well.
This is significant because scientists are eyeing the protein as a potential anticancer drug target. As Bhatia noted, mutations in the gene that guides production of the SHP2 protein can lead to blood cancers such as leukemia. Also, in solid tumors SHP2 often is hyperactivated and boosts tumor growth.
But the City of Hope team’s study found that the issue is more complicated than scientists may have thought. Depending on the type of cancer, suppressing the protein could cause anemia or other threatening complications.
Some blood cancers result from what are called “gain-of-function” mutations in SHP2, the researchers explain. These mutations cause SHP2 to become hyperactive, which leads to a cascade of molecular activity that can lead to cancer.
The current study — the first to examine the role of SHP2 in the development of adult human blood and immune system cells — showed that inhibiting SHP2 activity suppresses normal production of these cells in adults. On the other hand, cells with gain-of-function SHP2 mutations show increased dependency on SHP2 compared to normal cells.
“These results suggest that drugs designed to inhibit SHP2 may be toxic to normal bone marrow cells,” Bhatia said. “However targeting these drugs to cancers with gain-of function SHP2 mutations may allow more selective inhibition of cancer cells.”
The researchers hope to develop a screening method to determine the sensitivity of different cancer types to SHP2 inhibition, so that emerging SHP2 inhibitors can be used safely. SHP2 is part of a family of substances called protein tyrosine phosphatases, and the first drugs that target these proteins began study in clinical trials within the last few years.
Other researchers on the study include Hardik Modi, Tinisha McDonald, John Rossi, Ph.D., and Jiing-Kuan Yee, Ph.D.
The study was funded by the National Institutes of Health.