Despite years of research, glioblastoma, the most common and deadly brain cancer in adults, continues to outsmart treatments targeted to inhibit tumor growth.
Biologists and oncologists have long understood that a protein called the epidermal growth factor receptor or EGFR is altered in at least 50 percent of patients with glioblastoma. Yet patients with glioblastoma either have upfront resistance or quickly develop resistance to inhibitors aimed at stopping the protein's function, suggesting that there is another signalling pathway at play.
Researchers from the Ludwig Institute for Cancer Research, the University of California, San Diego (UCSD) and Los Angeles (UCLA) and the University of S-o Paulo, Brazil published their findings on a mechanism that defines these types of resistance in the August 13 online issue of Proceedings of the National Academy of Sciences.
Previous research suggested that PTEN, a tumor suppressor gene, may be turned off in some cancer patients, disabling its function and potentially causing the resistance to EGFR inhibitors. "We asked ourselves, how is PTEN being modified? What is altering its function?," said Frank Furnari, PhD, corresponding author and Ludwig senior investigator based at UCSD.
The researchers focused on one type of modification called phosphorylation, the process by which some proteins are turned on and off. They mapped the sites where PTEN was changed or phosphorylated and subsequently developed an antibody that would recognize the PTEN protein when it was phosphorylated.
The team then put the antibody to the test. Together with Suely Marie, MD, at the University of S-o Paulo, they first evaluated a large series of clinical samples from patients with glioblastoma and found that the presence of phosphorylation was associated with shortened survival. Then with Paul Mischel, MD, at UCLA, they examined samples from a completely different series of patients who were EGFR positive and did not respond to EGFR-inhibitor treatment. The results confirmed that patients with modified PTEN had resistance to EGFR inhibitors.