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.
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.
The article Epigenetic Alteration Linked To Lung Cancer Relapse appeared first on What is Epigenetics?.