Study Illuminates How Cancers Evade EGFR Inhibitors

Many cancers are driven by EGFR, suggesting that blocking its activity should curb tumor growth. Often, however, treatments based on that principle don't work, and cell culture experiments might offer insight. They have shown that inhibiting EGFR triggers autophagy, a degradation pathway that helps cancer cells withstand nutrient-poor conditions. New research explains how: Autophagy initiation in cultured cells occurs independent of EGFR's kinase activity and requires the receptor to bind another oncoprotein, lysosome-associated protein transmembrane 4 beta (LAPTM4B).

“It's a very provocative study,” says David Salomon, PhD, section chief in the mouse cancer genetics program at the National Cancer Institute in Frederick, MD. “I think it has immense clinical implications.” Salomon was not involved in the new work.

The results grew out of findings by the same group, led by Richard A. Anderson, PhD, professor of pharmacology at the University of Wisconsin-Madison School of Medicine and Public Health. Those experiments showed that LAPTM4B enhances EGFR signaling by disrupting the receptor's trafficking and degradation.

While trying to flesh out the molecular mechanisms, the researchers discovered a second way by which LAPTM4B promotes cancer malignancy through EGFR. Using Western blots and immunofluorescence to monitor protein–protein interactions and autophagy in human epithelial cell lines, Xiaojun Tan, a PhD candidate in Anderson's lab and the first author on both papers, made a curious observation. When the cells are starved, inactive EGFR piles up in endosomes. There, the receptor binds LAPTM4B, the proteins stabilize each other, and together, they initiate autophagy, the researchers report.

They also showed that existing EGFR inhibitors induce autophagy through inactive EGFR, suggesting that some EGFR-driven cancers may escape treatment through this newly reported pathway. The mechanism operates independent of the receptor's kinase activity, which is targeted by current EGFR drugs.

Together, the two papers suggest that LAPTM4B enhances EGFR function whether the receptor is active or inactive, and both pathways encourage cancer malignancy. These findings point toward LAPTM4B as a promising new therapeutic target, says Tan.

In addition, the Cell report lends support to the use of combination therapies involving EGFR and autophagy inhibitors.

Clinical trials have begun investigating short-term administration of a known autophagy inhibitor, hydroxychloroquine, in tumors being treated with EGFR inhibitors. But “it's still early days,” says Sharon Gorski, PhD, a biologist at the BC Cancer Agency in Vancouver, Canada, who had no part in the research. “There are many questions about efficacy, tolerability, and what mutation profiles will respond to the treatment.” Regardless, she adds, the new work is “biologically fascinating and clinically relevant.”