Cancer cells 'addicted' to self-preservation process

A team of investigators at The Cancer Institute of New Jersey (CINJ); Rutgers, The State University of New Jersey; and Princeton University, have determined that cancer cells are "addicted" to a self-preservation process known as autophagy. They also showed that the inhibition of that process could prove to be a valuable treatment approach for aggressive cancers. CINJ is a Center of Excellence of UMDNJ-Robert Wood Johnson Medical School.

Autophagy is a cellular self-cannibalization process where cells eat themselves to survive starvation. Eileen White, PhD, associate director for basic science at CINJ, and collaborators previously discovered that cancer cells can take advantage of the autophagy survival pathway to aid their growth into tumors. In this new study, Dr. White and colleagues have found that cancer cells induce autophagy and this self-cannibalization process enables the growth of the most aggressive tumors.

The latest research, which appears online and in the March print editions of Genes & Development, focuses on cancer genes known as H-ras and K-ras that are activated in many aggressive cancers with poor prognoses. These cancers, which are acutely sensitive to autophagy inhibition, have high levels of autophagy that provide cancer cells with sufficient nutrition to survive by recycling parts of themselves. In collaboration with the Joshua Rabinowitz and Hilary Coller laboratories at Princeton University, investigators were able to show that autophagy in these aggressive cancers provides fuel to the powerhouses of the cell, the mitochondria. By spurring the mitochondria to generate a steady supply of energy for tumor cells, autophagy keeps those cells alive and growing. These tumor cells are "addicted" to autophagy to support the metabolism of cancer cells.

By identifying that this autophagy "addiction" is prevalent in cancers with Ras mutations, such as lung, pancreatic and colon, a metabolic vulnerability of cancer cells is revealed - a vulnerability the authors say can be utilized for cancer therapy. "What this finding suggests is that patients with these poor-prognosis cancers may benefit from treatment that targets autophagy inhibition," said White, an adjunct professor of surgery at UMDNJ-Robert Wood Johnson Medical School, and a professor of molecular biology and biochemistry at Rutgers University, who is the senior author of the research publication.

White further notes while exploration involving autophagy inhibition drugs can lead to a more individualized treatment approach, more needs to be done. "Ideally, further examination of the autophagy cycle will lead to the identification of a certain point along that pathway that will compromise cancer cell survival. Once illuminated, that step in the process can be exploited so that researchers can find ways to maximize the benefits of autophagy inhibitors and improve clinical outcomes," she stated.

"Especially for oncogenes, such as Ras, that cannot be directly targeted with current drugs, identifying associated metabolic vulnerabilities points to important therapeutic opportunities," added Rabinowitz, MD, PhD, CINJ member and associate professor of chemistry at the Lewis-Sigler Institute for Integrative Genomics at Princeton.