MD Anderson scientists have found a molecular signaling pathway that connects two known contributors to cancer cell growth and survival. They also showed that the active signaling network shortens survival of breast cancer patients.
The epidermal growth factor receptor (EGFR) tells the protein MCM7, through an intermediary, to fire up the very first step of DNA replication leading to cell growth, the researchers report in the June issue of Cancer Cell.
"MCM7 overexpression is a marker of cell proliferation and is associated with glioblastoma and colorectal, ovarian and esophageal cancers, among others, yet the mechanisms that regulate its function have been unclear," said co-lead author Tzu-Hsuan Huang, Ph.D., formerly of MD Anderson's Department of Molecular and Cellular Biology and now with Amgen, Inc., in Boston.
EGFR to Lyn to MCM7 equals cancer cell growth
In a series of experiments, Huang, co-lead author Longfei Huo, Ph.D., a research scientist in Molecular and Cellular Biology, and colleagues tracked the signaling cascade from EGFR activation to activation of another signaling molecule called Lyn to MCM7 ignition. They found all three actions are correlated in human lung and breast cancer tumors.
Mice with high expression of either Lyn or MCM7 had breast cancer tumor volumes two to three times greater than those with low expression.
"We established that this signaling pathway correlates with EGFR status and poor survival in breast cancer patients," said study senior author Mien-Chie Hung, Ph.D., chair and professor of the department and holder of the Ruth Legett Jones Distinguished Chair.
An analysis of Lyn status in tumors of 125 breast cancer patients and MCM7 status in 120 patients showed substantially higher survival rates for those with low expression of either protein. In both cases, about 60 percent of those with high expression of Lyn or MCM7 survived to 75 months, compared to about 80 percent of those with low levels of the proteins.
Tumors often become resistant to drugs that target EGFR, Hung noted, so Lyn provides a target downstream from EGFR that might be effective when EGFR inhibitors fail. And the signaling network might be a resistance pathway that overcomes EGFR-inhibiting drugs.
Lyn-inhibiting drugs are on the way
Lyn inhibitors have been tested preclinically and in an early stage clinical trial, Huang said. They are not generally available yet but remain under development. Combining Lyn and EGFR inhibitors could have a heightened effect on EGFR-driven cancers.
"Lyn overexpression might be indispensable for cancer cells that rely on EGFR signaling to proliferate," Hung noted. Other researchers have shown that knocking out Lyn has less effect on cancer cell lines that are less dependent on EGFR to survive and grow.