A new set of drugs exploit a recently-revealed weakness in 'zombie-like' – or senescent – cells that could lead to new treatments for cancer and age-associated diseases. The study from the MRC Laboratory of Medical Sciences (LMS) and Imperial College London shows that senescent cells walk a tightrope, risking cell death with high levels of iron and other damaging agents but compensating for this by overproducing a protective protein that staves off death. Targeting this defence mechanism removes their shield and could be used to treat senescence-associated diseases, including cancer. This approach could complement existing treatments to bring much-needed improvements for cancer patients.
Cancers grow as a result of unconstrained cell division. But within most tumours, there is a portion that does not divide at all: senescent cells. Chemotherapy often increases the proportion of senescent cells in a tumour as it aims to stem the rapid proliferation, but although these cells don't directly increase the size of a tumour, they wreak havoc in their own way. Senescent cells, which are also a defining feature of aging conditions such as fibrosis, influence neighbouring cells by secreting molecules that increase proliferation, the spread of the cancer, and unwanted immune system activity. There is therefore an increasing interest in developing drugs that directly target and kill senescent cells, in cancer and beyond.
Mariantonietta D'Ambrosio, a postdoctoral researcher at the LMS, is lead author of the study published in Nature Cell Biology which reveals a new approach to killing senescent cells in cancer. Mariantonietta explains: "Senescence was considered for a long time to be positive, because senescent cells don't proliferate, which is the core feature of cancer. Normal chemotherapy induces senescence blocking the proliferation of cancer cells, so the tumour doesn't get bigger. But with time you also see the negative side of the senescent cells, because they secrete a lot of factors that influence neighbouring cells and induce even more proliferation, metastasis, and recruitment of bad parts of the immune system that will provoke even more aggressiveness in the tumour. For this reason, we tried to find some drugs that were able to kill the senescent cells."
Testing 10,000 possible drugs
The researchers cast a broad net in their search for new drugs that might kill senescent cells. Together with collaborators at the Department of Medicinal Chemistry at Imperial, they decided to examine a class of inhibitors usually referred to as 'covalent compounds'. These compounds can form a covalent bond with their target, which can result in the inhibition of proteins previously considered undruggable. They introduced 10,000 different covalent compounds to both senescent cells and normal cells, looking for the ones that preferentially killed senescent cells and classing the drug as 'senolytic', or senescent-killing.
They narrowed their results down to just four promising compounds and found that three of them affected a particular protein: GPX4. GPX4 has a protective role in cells, helping stave off ferroptosis, a type of cell death associated with high levels of iron and destructive 'reactive oxygen species'. Ferroptosis had only recently been revealed as a potential weakness of senescent cells.
Mariantonietta says, "recent papers have shown this predisposition of senescent cells to ferroptosis, but it's a new senescence vulnerability. That creates an opportunity for us to exploit. So now there is research to find senolytic drugs to kill cells through ferroptosis."
To protect themselves against the high levels of iron and other ferroptosis-causing agents, senescent cells have high levels of GPX4. It's like proactively taking a painkiller so you can keep running on an ankle; the damage and danger remains, but the immediate risks are bypassed. Removing the painkiller makes the pain unbearable. And blocking the activity of GPX4, as the drugs identified by the screening process do, removes the shield, making fatal ferroptosis unavoidable.
Improved outcomes in three cancer models
The team tested their drugs with three different mouse models of cancer and saw improved outcomes as a result of senescent cell death in each case. Translating this to patients could be a huge asset to cancer treatments.
"In mouse models we saw that these drugs reduced tumour size, and improved survival. Now we need to see the effect on the immune system. Is the improvement also awakening the 'good side' of the immune system (T cells, natural killer cells) that helps to kill the tumour?" says Professor Jesus Gil, senior author and Head of the Senescence group at the LMS, "Once we know more, the next step is to understand which cancer cell types or specific patients might better respond to this treatment. For example, if a patient undergoing chemotherapy overexpressed GPX4 then you could use this approach in combination with existing drugs to improve efficacy."
This approach offers a much-needed new perspective on cancer therapy, pinpointing senescent cells as an underexploited target. Mariantonietta says it has potential to transform treatment: "Targeting senescence is a huge opportunity for cancer treatments, and ultimately it can play a supporting role in addition to chemotherapy and immunotherapy."
Researchers at several institutions, including the Institute of Oncology Research (IOR) in Bellinzona, Switzerland and the M3 Research Centre at the University of Tübingen in Germany also contributed to this study.
