Researchers at the University of Texas Southwestern Medical Center have revealed that overactivity of a protein called the epidermal growth factor receptor (EGFR) quickens tumor growth and chemotherapy resistance. The study was led by Dr. Beth Levine, director of the Center for Autophagy Research and a Howard Hughes Medical Institute (HHMI) investigator at UT Southwestern. It was published on September 12th in the journal Cell.
Researchers found that EGFR turns off autophagy by binding to a protein called beclin1, which switches on autophagy. Autophagy is a process by which cells recycle unneeded parts. Abnormally high levels of EGFR leads to more rapid tumor growth and chemotherapy resistance, which was confirmed in mouse models with non-small lung carcinoma cells and many types of cancer cells.
“The fact that this type of cell surface receptor can directly interact with Beclin 1 and shut off autophagy provides fundamental insight into how certain oncogenes may cause cancer,” said Dr. Levine, “Our findings suggest that inactivation of autophagy may be a critically important factor in the progression of lung cancer.”
Previously, Dr. Levine identified beclin 1 as the first mammalian gene shown to function in autophagy. Dr. Levine suggested that defects in this gene may contribute to cancer, ageng, neurodegenerative disease and anti-infectious diseases. The findings will give insights about how EGFR-inhibitors work combating cancer, which had been remained as mystery.
Today some related clinical trials are ongoing to test inhibitors of autophagy as a means of overcoming the chemotherapeutic resistance. However, unexpectedly, Dr. Levine’s study found the opposite thing that autophagy inhibition may actually worsen chemotherapy outcomes for patients with specific cancer mutations.
“We have oral medications that achieve dramatic clinical benefit and increase survival in this subset of patients, but even these successfully treated patients eventually become resistant to the treatment,” said Dr. John Minna, director of the Nancy B. and Jack L. Hamon Center for Therapeutic Oncology Research. “These new findings are important for two reasons: First, they provide insight into how to extend EGFR-targeted therapy to a much larger group of lung cancer patients, including those whose tumors do not have mutations. Second, they provide a totally new approach to overcoming resistance to EGFR-targeted therapy.”
Photo from http://clincancerres.aacrjournals.org