Lung cancer is the leading cause of cancer death worldwide and even today only 10% of people survive lung cancer for 10 years or more in the UK. 

One challenge in treating lung cancer is that lung cancer cells can enter a sleep-like state called quiescence. Healthy cells can enter quiescence in response to damage to their DNA. This is an important mechanism for maintaining the stability of our genomes by providing cells with the chance to repair damaged DNA and to prevent mutations arising. However, in cancer, this same sleeping state allows cells to ‘hide’ from therapies and begin rapidly proliferating again after treatment ends, causing cancer to come back – or relapse. This is why even when patients with lung cancer initially respond to therapy, they frequently relapse and have very poor chances of survival. 

Research published recently in the British Journal of Cancer by Dr Alexis Barr and Stephen Cutty of the Cell Cycle Control Group at the LMS and Imperial College London has shown blocking a protein called p21 prevents lung cancer cells from entering this sleeping state, leading to more cancer cell death before and after chemotherapy treatment and reducing the chance of cancer relapse. 

p21 is an important protein that regulates cell growth and proliferation through its effects on the cell cycle. It stops cell proliferation by inhibiting the enzymes that drive cells to replicate and divide. Despite being a cell cycle inhibitor, high levels of p21 have been observed in the most common type of lung cancer which makes up around 85% of all lung cancer cases, called non-small cell lung cancer (NSCLC). Surprisingly, high p21 levels are associated with a poor prognosis in these patients, suggesting that p21 provides cancer cells with a survival advantage rather than stopping cancer cells proliferating.  

In 2017, Alexis published work showing that healthy cells can enter a spontaneous sleeping state in response to damaged DNA that is mediated by p21. This led Alexis to hypothesise that NSCLC cells retain the ability to enter this p21-mediated sleeping state, giving them time to recover from damage caused by cancer drugs before starting to proliferate again after treatment ends.  

Working in human NSCLC cells, the team showed that removing the p21 gene stopped cells entering the sleeping state. This led to a higher level of DNA damage and increased cell death. To determine whether the ability of cells to enter the sleeping state would make a difference to their response to therapy, the team modelled cancer relapse in the laboratory by testing chemotherapy agents on NSCLC cells with and without p21. They found that cells which lacked p21 died more before and after treatment compared to cells with p21. Importantly, very few cells lacking p21 could start proliferating again after treatment ended, suggesting that cancer cells without p21 function would not be able to relapse. Blocking p21 therefore provides a huge therapeutic potential for improving people’s response to lung cancer treatment and stopping people’s cancer from coming back in the future, which would greatly improve outcomes. 

“Cancer Research UK identified lung cancer as a cancer of unmet need, where new therapies are desperately sought. 80% of patients present with inoperable disease and are essentially incurable. Even if patients do respond to therapy, they frequently relapse with resistant disease,” says Alexis, “We are really excited about the prospect of inhibiting p21 to improve the survival of lung cancer patients. It’s not an easy protein to target but we have some ideas up our sleeves and are already making progress in this area. Watch this space!” 

Working with colleagues across Imperial College London and the Institute of Cancer Research, Alexis’ team is now developing p21 inhibitors which could be given alongside chemotherapy. If the team can successfully develop drugs that can inhibit p21 in the lab, the next step would be to begin testing them in preclinical models such as mice.  

Although the researchers stress the work is at an early stage, around half of patients with NSCLC have this ability to enter the p21 mediated sleeping state meaning that the development of p21 inhibitors could benefit a large proportion of the patient population. New treatments such as these are urgently needed to improve outcomes for people with lung cancer and to increase their quality of life.  

Cutty, S., Hughes, F., Ortega-Prieto, P. et al. Pro-survival roles for p21(Cip1/Waf1) in non-small cell lung cancer. Br J Cancer (2024). https://doi.org/10.1038/s41416-024-02928-9

Published 20 December 2024