Scientists catch EGFR passing a crucial message to cancer-promoting protein

June 18, 2013

Researchers have discovered and mapped the signaling network between two previously unconnected proteins, exposing a link that, if broken, could cut off cancer cell growth at its starting point.

A team led by scientists at The University of Texas MD Anderson Cancer Center reported the tie between epidermal growth factor receptor (EGFR), a well-known cancer , and MCM7, a protein vital to the first step in DNA replication, in the June issue of Cancer Cell.

"MCM7 overexpression marks 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.

MCM7 is important to DNA licensing, Huang said, "which is the very first step in DNA replication and, in effect, gives the machinery permission to proceed." Its function had not previously been tied to EGFR , which leads to and cell growth, and is often dysfunctional in human cancers.

EGFR tells Lyn to tell MCM7 to fuel cancer growth

In a series of experiments, Huang, co-lead author Longfei Huo, Ph.D. a research scientist in , and colleagues tracked the signaling cascade from EGFR activation to activation of another signaling molecule called Lyn to MCM7 ignition.

Both EGFR and Lyn are , which activate other proteins by attaching phosphate groups to them. The team found that activated EGFR phosphorylates Lyn, which in turn tags MCM7 with phosphate groups. They found all three actions are correlated in human lung and 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.

Pathway shortens patient survival

"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.

Drugs that target EGFR often become less effective over time, Hung noted, so Lyn provides a target downstream from EGFR that might be effective. And the signaling network might be a resistance pathway that overcomes EGFR-inhibiting drugs.

Lyn-inhibiting drugs are under development

Lyn inhibitors have been tested preclinically and in an early stage clinical trial, Huang said. They are not generally available as they're still 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.

Explore further: When oxygen is short, EGFR prevents maturation of cancer-fighting miRNAs

Related Stories

When oxygen is short, EGFR prevents maturation of cancer-fighting miRNAs

May 23, 2013
Even while being dragged to its destruction inside a cell, a cancer-promoting growth factor receptor fires away, sending signals that thwart the development of tumor-suppressing microRNAs (miRNAs) before it's dissolved, researchers ...

The right combination: Overcoming drug resistance in cancer

June 1, 2012
Overactive epidermal growth factor receptor (EGFR) signaling has been linked to the development of cancer. Several drug therapies have been developed to treat these EGFR-associated cancers; however, many patients have developed ...

Some patients with treatment-resistant colorectal cancers may have a new option

June 2, 2013
A subset of colorectal cancers responds to anti-epidermal growth factor receptor (anti-EGFR) therapies, but develops resistance within months. Among cancers that develop resistance to anti-EGFR therapy, some showed overexpression ...

A hijacking of healthy cellular circuits

April 8, 2013
Proteins that control cell growth are often mutated in cancer, and their aberrant signaling drives the wild proliferation of cells that gives rise to tumors. One such protein, the epidermal growth factor receptor (EGFR), ...

EGFR mutation not prognostic factor in non-small cell lung cancer

January 15, 2013
Recent studies have demonstrated that molecular-targeted agents, such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), may prolong survival of selected patients based on tumor biomarkers. The presence ...

Recommended for you

Study may explain failure of retinoic acid trials against breast cancer

July 25, 2017
Estrogen-positive breast cancers are often treated with anti-estrogen therapies. But about half of these cancers contain a subpopulation of cells marked by the protein cytokeratin 5 (CK5), which resists treatment—and breast ...

Physical activity could combat fatigue, cognitive decline in cancer survivors

July 25, 2017
A new study indicates that cancer patients and survivors have a ready weapon against fatigue and "chemo brain": a brisk walk.

Breaking the genetic resistance of lung cancer and melanoma

July 25, 2017
Researchers from Monash University and the Memorial Sloan Kettering Cancer Center (MSKCC, New York) have discovered why some cancers – particularly lung cancer and melanoma – are able to quickly develop deadly resistance ...

New therapeutic approach for difficult-to-treat subtype of ovarian cancer identified

July 24, 2017
A potential new therapeutic strategy for a difficult-to-treat form of ovarian cancer has been discovered by Wistar scientists. The findings were published online in Nature Cell Biology.

Immune cells the missing ingredient in new bladder cancer treatment

July 24, 2017
New research offers a possible explanation for why a new type of cancer treatment hasn't been working as expected against bladder cancer.

Anti-cancer chemotherapeutic agent inhibits glioblastoma growth and radiation resistance

July 24, 2017
Glioblastoma is a primary brain tumor with dismal survival rates, even after treatment with surgery, chemotherapy and radiation. A small subpopulation of tumor cells—glioma stem cells—is responsible for glioblastoma's ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.