Chemotherapy has been the mainstay for lung cancer treatment for decades. Unfortunately, even after an initial positive response to it, tumors can sometimes develop drug resistance. When this happens, there is little doctors can do to improve a patient’s outcome, as the survival rate after relapse can be devastatingly low. Understanding exactly what causes this cancer to rebound has scientists taking a closer look at the genetic diversity of lung tumors, in particular their epigenetic signature.
In recent years, genomic profiling and mutational analysis have increased interest in developing therapies that target the genetic as well as epigenetic mutations in many types of cancers, including lung cancer. In the context of non–small cell lung cancer (NSCLC), the most common form, approximately 15–30% of patients show a mutation in the EGFR gene that regulates tumor growth. Although effective treatments are available that can destroy cancer cells with this oncogenic mutation, tumors can grow back. Researchers at Cold Spring Harbor Laboratory (CSHL) set out to investigate why this happens by examining the molecular mechanisms that lead to the occurrence of drug resistance in EGFR mutation-positive NSCLC.
In their paper published online in eLife, the researchers studied another gene, AXL, which regulates various cellular responses, including cell survival. It has also been observed as augmented in cancers that develop drug resistance. CSHL scientists and author Raffaella Sordella and her team found that AXL-positive cells are pre-existing in a subpopulation of cancer cells, and they don’t need to rely on EGFR for survival. They are also produced by an epigenetic/stochastic mechanism that makes them highly plastic, capable of transitioning between drug-resistant and drug-sensitivity states. After EGFR treatment is done, the remaining cells continue to fluctuate with random modifications, allowing for both kinds of cells to grow back.
Drug resistance in recent years has become a problem, fueling more epigenetic studies like this to provide answers and potential solutions. In previous articles, we have discussed how certain diseases like ovarian cancer, tuberculosis, and malaria can develop drug resistance and how certain epigenetic mechanisms such as DNA methylation and histone modifications may be involved.
Working with the clinicians at Northwell Health and Professor Gregory Hannon at the Cancer Research UK Cambridge Institute, the researchers determined that the AXL-positive cell state had a unique microRNA cell signature, regulated epigenetically by DNA methylation. Micro RNAs are molecules involved in regulating gene expression via managing how genes are copied or transcribed.
“The genome is like a library,” explains Sordella. “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.”
The particular microRNA involved here is called miR-335, and it controls cancer cell state. The researchers tested whether miR-335 regulates the development of AXL-positive cells and found it does. When a cancer cell loses this molecule, a series of events are triggered that caused the cells to choose an alternative AXL pathway. Thus, instead of being destroyed by EGFR drug treatments, the cells survive, causing the tumor to return.
The key to eliminating relapse for this type of lung cancer is figuring out how to stop the tumor growth. Although more research is needed, the findings from this study could have important clinical applications. The researchers anticipate some type of co-treatment for tumors with drugs that inhibit both EGFR and AXL to wipe out all chances of tumor resurgence from the beginning.
Source: P.S. Tepes et al. (2021). An epigenetic switch regulates the ontogeny of AXL-positive/EGFR-TKi-resistant cells by modulating miR-335 expression. eLife.
Reference: Preventing lung cancer’s unwelcome return, Cold Spring Harbor Laboratory. July 13, 2021.