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When a doctor gives a patient antibiotics for a bacterial infection, they usually ask them to complete the entire course of treatment, even when the symptoms go away. This is to make sure that the drugs kill any remaining bacteria. Cold Spring Harbor Laboratory (CSHL) guest scientist Raffaella Sordella has studied a similar problem that occurs in some lung cancers.
About 15% of non-small cell lung cancers have a mutation in a growth receptor called EGFR, causing tumor cells to grow out of control. Researchers have developed an effective drug that inhibits EGFR and kills cancer cells, but the tumor grows back later. Sordella wanted to understand the molecular mechanisms behind this relapse and how to prevent it.
Sordella and his team found that a small percentage of drug-resistant cancer cells were already present before treatment. Instead of relying on EGFR, these cells depend on another gene (AXL) for their survival. In addition, they observed that cells could transition between these drug-sensitive and drug-resistant “states”. When patients complete EGFR treatment, random changes constantly occur in the remaining cells, causing both types of cells to regrow.
Sordella and her team worked with clinicians from Northwell Health and former CSHL professor Gregory Hannon, now at Cancer Research UK Cambridge Institute. Hannon’s research focuses on microRNA, a molecule that regulates cells by handling transcribed (copied) genes. Sordella explains:
“The genome is like a library. So when you have to make a recipe to cook something, you go in there, you transcribe your recipe, you take it out of the library, you go into the kitchen. What these microRNAs do. , they intercept every recipe that comes out of your library. And then they decide whether it’s a recipe that the cell should care about or not. So they are what they call the “keepers.” of a cell state. “
Researchers have found that a certain microRNA called 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 alternate 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 arises in lung cancer is essential in determining how to clear a tumor. Sordella hopes that these findings could help develop treatments to eliminate the cells dependent on AXL and EGFR early on.
Reference: Safaric Tepes P, Pal D, Lindsted T, et al. An epigenetic switch regulates the ontogeny of EGFR-TKI positive / resistant AXL cells by modulating the expression of miR-335. eLife. 2021; 10: e66109. doi: 10.7554 / eLife.66109
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