Gene found that causes EGFR-driven lung cancer to return after treatment

About 15% of non-small cell lung cancers have a mutation in a growth receptor called EGFR, which causes tumor cells to grow uncontrollably. Researchers developed an effective drug that inhibits EGFR and kills cancer cells. However, the tumors can grow back.

A team from Cold Spring Harbor Laboratory (CSHL) wanted to understand the molecular mechanisms behind this relapse and how to prevent it. The researchers discovered that a small percentage of resistant cancer cells were already present before the treatment. In addition, their findings suggest that microRNA miR-335 expression determines the “state” of the cancer cells. This one work has been published in eLife, in the newspaper.
Watch Free Movies and TV shows Apps

🎬📺 Free Movies and Free TV Shows! 🎭🎬

About 15% of non-small cell lung cancers have a mutation in a growth receptor called EGFR, which causes tumor cells to grow uncontrollably. Researchers developed an effective drug that inhibits EGFR and kills cancer cells. However, the tumors can grow back.

Raffaella Sordella, Ph.D., visiting scientist at CSHL found that a small percentage of resistant cancer cells were already present before treatment. Rather than relying on EGFR, these cells depend on the AXL gene for survival. In addition, Sordella and colleagues noted that the cells were able to switch between these drug-sensitive and drug-resistant “states.” When patients finish treatment, random changes take place in the remaining cells, causing both types of cells to regrow.

The authors noted that “elevated levels of AXL and GAS6 induce resistance to EGFR tyrosine kinase inhibitors such as Erlotinib and Osimertinib in certain tumors with mesenchymal-like features.”

By studying the development of AXL-positive cells, the researchers identified a novel mechanism of drug resistance based on cell-state transition. More specifically, they show that “AXL-positive cells are already present as a subpopulation of cancer cells in erlotinib-naive tumors and tumor-derived cell lines and that AXL expression is regulated by a mechanism targeting the epigenetic regulation of miR- 335.”

“The genome is like a library,” Sordella explains. “So if you have to make a recipe to bake something, you go there, you write out your recipe, you get it from the library, you go into the kitchen. What these microRNAs do, they intercept all the recipes that come out of your library. And then they decide whether this is a recipe the cell should care about or not. So they are what they call ‘gatekeepers’ of a cell state.”

miR335 determines the “state” of the cancer cell. If the cancer cell loses miR335, a cascade of events is triggered that allows cells to use the alternative AXL pathway; the cells are not killed by drugs that target EGFR. These drug-resistant cells survive and eventually the tumor grows back.

Understanding how resistance develops in lung cancer is key to figuring out how to eliminate a tumor. Sordella hopes these findings can help develop treatments to eradicate both AXL- and EGFR-dependent cells from the get-go.

Leave a Comment