Loss of anti-tumor protein may cause resistance to certain cancer therapies

December 21, 2020

HERSHEY, Pa. -- The absence of a protein that works to prevent tumor formation may explain why some patients are resistant to a common cancer therapy, according to Penn State College of Medicine researchers. They said that testing cancers for the presence of this protein may help clinicians identify patients who may be resistant to or relapse when treated with the therapy.

Epidermal growth factor receptor (EGFR) is a protein that plays a role in cell division and survival signaling and is active in skin, bladder, esophageal, lung, liver, pancreatic, colon, and head and neck cancers. Patients with high amounts of this protein in their tumors tend to have a poor prognosis. EGFR-targeting therapies are used in clinical practice and are often initially effective in many patients. However, some patients are resistant to the therapy and many who were initially responsive to treatment relapse within a year.

Douglas Stairs, assistant professor of pathology and laboratory medicine and pharmacology, investigated why these patients may be resistant to EGFR therapies. He said mutations in the gene that contains the instructions for building EGFR or other genetic and cellular factors account for about 70% of resistance causes.

"There are still some reasons for resistance that are alluding scientists," said Stairs, a Penn State Cancer Institute researcher. "Our previous work showed that too much EGFR and reduced amounts of a protein called p120 catenin (p120ctn) can cause cancer to develop. We hypothesized that reduced amounts of p120ctn might also cause resistance to EGFR therapies."

In healthy cells, p120ctn strengthens cell-to-cell contact by cooperating with other proteins to strengthen connections between epithelial cells, which serve as the barrier between the body's external and internal surfaces. According to Stairs, scientists know that the cancer cells often have reduced amounts of p120ctn, but are unsure why.

To test their hypothesis, Stairs and colleagues cultured genetically-engineered esophageal cancer cells -- one set with normal amounts of EGFR and p120ctn, one set with higher amounts of EGFR, one set with lower amounts of p120ctn and another set with high amounts of EGFR and low amounts of p120ctn. They then treated each cell line with a series of EGFR-targeting therapies.

Cells with high amounts of EGFR died when treated with the therapies, while those with normal amounts of EGFR were not affected by the therapies. The cell lines that had high amounts of EGFR and reduced amounts of p120ctn were resistant -- demonstrating that loss of p120ctn is a critical component to the cells' resistance to EGFR-targeted therapies. The results were published in PLOS ONE.

Stairs said that while these results are promising, his lab will continue to explore the role of p120ctn loss in EGFR therapy resistance by testing the effect in cancer cells sampled from patients with colon, lung, oral or other cancers. They will also explore whether the cells with increased EGFR and decreased p120ctn are resistant to other EGFR therapies approved by the U.S. Food and Drug Administration.

"We also need to investigate further how the loss of p120ctn causes this resistance," Stairs said. "For now, we know that if patients who have high levels of EGFR in their samples were also tested for their levels of p120ctn, it may provide a clue to clinicians as to which patients are at risk for resistance to EGFR-targeting therapies or relapse."
Mary Landmesser and Wesley Raup-Konsavage of Penn State College of Medicine and Heather Lehman of Millersville University also contributed to this research.

This research was supported by a Research Scholar Grant (RSG-16-219-01-TBG) from the American Cancer Society, a Department of Pathology Researcher-Initiated Grant, and both a Development Award and Program Project Award from the Penn State Cancer Institute and Highmark Community Health Reinvestment Grant. The authors have declared no conflicts of interest.

Penn State

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.