MicroRNA, AXL Gene Potentially Responsible for Drug Resistance in Certain Non-Small Cell Lung Cancers

Investigators have found that a small percentage of epidermal growth factor receptor (EGFR) inhibitor-resistant cancer cells are present in certain patients with non-small cell lung cancers (NSCLCs), potentially explaining tumor regrowth in these patients, according to a study published in eLife. Mutations in the EGFR growth receptor occur in approximately 15% of NSCLCs, according to the study.

The study results indicate that these drug-resistant cells rely on a different gene—AXL—for survival instead of EGFR. The investigators further observed that cancer cells could transition between drug-sensitive and drug-resistant states, and that when patients finish EGFR treatment, random modifications constantly occur in the remaining cells, which causes both types of cells to grow back.

Gregory Hannon, FRS, FMedSci, one of the study’s investigators, conducts research mainly focused on microRNA, a molecule that regulates cells by managing transcribed genes. The investigators found that a specific mircoRNA—miR335—determines the state of the cancer cell.

If miR335 is lost, the cell undergoes a cascade of events leading to the use of the AXL pathway, and these cells are no longer killed by drugs targeting EGFR. These drug-resistant cells are able to survive treatment with EGFR inhibitors, allowing the tumor to eventually grow back, according to the researchers.

“The genome is like a library,” said Raffaella Sordella, PhD, in a press release. “So, when you have to do a recipe to bake something, you go there, you transcribe your recipe, you take it out from the library, you go in the kitchen. What these microRNAs do, they intercept all the recipes that are getting out from your library. And then, they decide whether this is a recipe that the cell should care about or not. So, they are what they call 'gatekeepers' of a cell state.”

According to the study authors, understanding the mechanisms by which drug resistance arises in lung cancer is critical to determining how to eliminate a tumor. They expressed hope that these findings would allow further research to develop treatments that can target both AXL- and EGFR-dependent cells from the start, potentially preventing tumor regrowth entirely.

REFERENCE

Preventing lung cancer's unwelcome return [news release]. ScienceDaily; July 13, 2021. Accessed July 22, 2021. https://www.sciencedaily.com/releases/2021/07/210713145827.htm