Targeting Cancer Cell Fuel Supply May Stop Growth

In a new study published in Genes & Development, researchers identified a new approach to cancer therapy that involves cutting off a cancer cell’s fuel supply by targeting autophagy.

Autophagy is a cellular survival mechanism where cells eat themselves in times of starvation and stress. The primary focus of the study was on lung cancers driven by the Kras protein.

About 85% to 90% of lung cancers are non-small cell lung cancer (NSCLC), and have a poor response rate to standard treatment. Mutations in the Ras protein family, which includes Kras, are frequently detected in NSCLC, but unfortunately drugs that target Ras mutations in NSCLC have not been effective.

“It was long believed that autophagy allows cells to digest and recycle part of themselves to support their metabolism and survive interruptions in their supply of nutrients,” said co-corresponding study authors Eileen P. White, PhD, and Jessie Yanxiang Guo, PhD. “But whether this is true, and what the recycling was needed for, was not known.”

In addition to regular cells, autophagy is also turned on by cancer cells and used to survive. This is a process that is used even more so by cancer cells than normal cells, the study authors noted.

Previously, researchers discovered that cancer cells are activated by the Ras protein family required autophagy for cell maintenance, metabolic stress tolerance, and tumor development. When the Ras proteins were switched on, they were able to turn on other proteins that could activate genes responsible for cell growth and survival.

By understanding the critical cellular process of autophagy and its role in Kras-driven tumor cells, it may lead to new therapeutic approaches for NSCLC. In the collaborative study, researchers investigated how autophagy enables cancer cells to survive stress.

They used tumor derived cell lines generated from genetically engineered mouse models for Kras-driven NSCLC. A technique called mass spectroscopy was then used to trace the path of intracellular components cannibalized by autophagy.

“We found that cancer cells do indeed breakdown and recycle themselves to survive starvation,” White and Guo said. “This cannibalization of cellular parts provides fuel to the powerhouses of the cell, the mitochondria, to maintain their energy levels. Thus, blocking autophagy cuts of the fuel supply to the powerhouses, creating an energy crisis and ultimately cancer cell death.”

The findings suggest that by blocking autophagy, and in turn cutting off the fuel to cancer cells, it could be a potential therapeutic strategy for Kras-driven lung cancers. However, investigators indicated that future research needs to be done to clarify whether autophagy pathways can be applied to other types of cancer.