Washington DC: Researchers uncovered a powerful weakness in lung cancer by shutting down a protein that helps tumours survive stress.
When this protein, FSP1, was blocked, lung tumours in mice shrank dramatically, with many cancer cells essentially triggering their own self-destruct mode. The work points to a fresh strategy for targeting stubborn lung cancers.
Researchers at NYU Langone Health have identified how a specific form of cell death linked to the buildup of highly reactive molecules can slow the growth of lung tumours.
This type of cell death, known as ferroptosis, originally evolved as a way for the body to clear out cells that become overly stressed.
Cancer cells fall into this category, yet over time, they have developed ways to block ferroptosis so they can continue multiplying even under damaging conditions.
A study published online November 5 in Nature showed that an experimental therapy targeting a protein called ferroptosis suppressor protein 1 (FSP1) significantly reduced tumour growth in mice with lung adenocarcinoma (LUAD).
Blocking this protein, which helps cancer cells avoid ferroptosis, shrank tumours by as much as 80%.
Lung cancer remains the world’s leading cause of cancer-related deaths, and LUAD is the most common form among nonsmokers, accounting for about 40% of cases.
“This first test of a drug that blocks ferroptosis suppression highlights the importance of the process to cancer cell survival and paves the way for a new treatment strategy,” said senior study author Thales Papagiannakopoulos, PhD[GW1], an associate professor in the Department of Pathology[GW2] at the NYU Grossman School of Medicine.
Reactive Molecules and Their Role in Cell Damage
Ferroptosis takes place when iron levels rise inside cells, fueling the production of highly reactive molecules made from oxygen, water, and hydrogen peroxide known as reactive oxygen species (ROS).
In small amounts, ROS help cells communicate. In excess, they create oxidative stress, which occurs when ROS add oxygen molecules to vital proteins and DNA, damaging or breaking them apart. ROS can also harm fats that form the outer membranes of cells, contributing to cell death and tissue injury.
Blocking FSP1 Shows Strong Tumor-Suppressing Effects
To investigate how FSP1 affects lung cancer, the research team genetically modified mice so that their lung cancer cells lacked the FSP1 gene.
These mice developed smaller tumours due to increased cancer cell death. The researchers also tested icFSP1, a newer drug designed to inhibit FSP1.
Mice treated with icFSP1 lived longer and experienced tumour reductions similar to those seen in mice whose cancer cells were engineered to lack FSP1.
The study also found that FSP1 may be a more promising treatment target than another ferroptosis-blocking protein, glutathione peroxidase 4 (GPX4), which has been studied in cancer research for a longer period.
The findings suggest that FSP1 is more actively involved in preventing ferroptosis in lung cancer cells while playing a smaller role in normal cell function (which could translate to fewer side effects).
Increased levels of FSP1 were also associated with poorer survival rates in human LUAD patients, unlike GPX4.
Future Directions and Ongoing Research
“Our future research will focus on optimising FSP1 inhibitors and investigating the potential of harnessing ferroptosis as a treatment strategy for other solid tumours, such as pancreatic cancer,” said lead study author Katherine Wu, an MD/PhD student working in the Papagiannakopoulos lab.
“We aim to translate these findings from the lab into novel clinical therapies for cancer patients,” added author Katherine Wu.
