When a doctor administers antibiotics for a bacterial infection to a patient, the entire treatment usually needs to be terminated, even if the symptoms disappear. This is to ensure that the drug kills the remaining bacteria. Raffaella Sordella, a visiting scholar at the Cold Spring Harbor Laboratory (CSHL), investigated similar problems with some lung cancers.
About 15% of non-small cell lung cancers have a mutation in a growth receptor called EGFR that causes tumor cells to grow out of control. Researchers have developed effective drugs that block EGFR and kill cancer cells, but tumors grow later. Sordella wanted to understand the molecular mechanism behind this recurrence and how to prevent it.
Sordella and her team discovered that a small portion of drug-resistant cancer cells were already present before treatment. Instead of relying on EGFR, these cells depend on another gene (AXL) for survival. In addition, they observed that cells could transition between these drug-sensitive and drug-resistant “states.” When the patient finishes EGFR treatment, the remaining cells constantly undergo random changes and both types of cells are restored.
Sordella and her team worked with a Northwell Health clinician and former CSHL professor Gregory Hannon, now at Cancer Research UK Cambridge Institute. Hanon’s research focuses on microRNAs, which are molecules that regulate cells by controlling transcribed (copied) genes.
The genome is like a library. So when you have to make a recipe to bake something, you go there, you copy your recipe, you take it out of the library, you go to the kitchen. What these microRNAs do is intercept all recipes that come out of the library. And they decide if this is a recipe that cells should care about. In other words, they call them cell-state “gatekeepers.” “
Raffaella Sordella, Scientist
Researchers have discovered that a specific microRNA called miR335 determines the “state” of cancer cells. When a cancer cell loses miR335, a series of events is triggered, allowing the cell to use an alternative AXL pathway. Cells are not killed by drugs that target EGFR. These drug-resistant cells survive and eventually the tumor recovers.
Understanding how resistance develops in lung cancer is the key to understanding how to eliminate the tumor. Sordella hopes that these findings will help develop treatments that will wipe out both AXL-dependent and EGFR-dependent cells from the ground up.
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