Those results, published March 7 in PNAS, show that upregulation of HER3 limits the effectiveness of HER2-targeted therapies and that a combination of drugs that target both HER2 and HER3 should be considered for optimal clinical benefit.
Since PI3K/Akt is the key pro-survival signaling pathway downstream of HER2, the investigators also examined the utility of inhibitors of PI3K in HER2-positive breast cancer cells.
Those experiments, led by postdoctoral fellow Anindita Chakrabarty, Ph.D., and published Feb. 28 also in PNAS, showed a similar upregulation of HER3 in response to treatment with a PI3K inhibitor currently in clinical development. In turn, this compensatory upregulation of HER3 partially reactivated the PI3K/Akt pathway and limited the action of the PI3K inhibitor.
"This shows that therapeutic use of PI3K inhibitors would be limited if used as single agents in HER2-positive cancers. These results have implications for other cancers treated with this class of drugs," Arteaga said. However, he notes PI3K inhibitors might have clinical merit when used in combination with HER2-HER3 antagonists.
Since both HER3 inhibitors and PI3K inhibitors are now in clinical development, "these studies provide a scientific rationale for how a combination of the new drugs with HER2-targeted therapies might be used to provide better results for many patients with breast cancer," Arteaga said.
|Contact: Melissa Marino|
Vanderbilt University Medical Center