Researchers at Durham University, working with Pleco Therapeutics (Netherlands), have uncovered a surprising new reason why some lung cancers stop responding to chemotherapy: the combined action of several different metals inside tumour cells.

While metals such as copper, zinc and iron are already known to influence cancer, most previous studies have looked at one metal at a time.

The new research shows for the first time that combinations of metals can cooperate to make lung cancer cells highly resistant to treatment even when each metal alone has little effect.

The study focused on metals commonly linked to smoking and environmental pollution, including copper, manganese, zinc, chromium, cadmium and lead.

Researchers found that low, non-toxic levels of these metals could build up inside lung cancer cells and dramatically reduce the effectiveness of several commonly used chemotherapy drugs.

Importantly, the resistance was reversible. The research team identified a small molecule called MiADMSA, originally developed to treat metal poisoning, which was able to enter cells and remove multiple metals at once.

When used alongside chemotherapy, MiADMSA restored treatment sensitivity in laboratory-grown lung cancer cells and significantly reduced tumour growth in mouse models exposed to metals.

The findings suggest that the metal environment inside tumours may play a major role in whether chemotherapy succeeds or fails.

Lead author of the study Dr Patricia Muller of Durham University, said: “We’ve found that metals inside tumour cells can work together to block chemotherapy, but the exciting part is that this resistance can be reversed.

“Using MiADMSA, a metal-binding compound that removes multiple metals from cells, we were able to restore treatment sensitivity.

“These findings open up an exciting opportunity to develop combination therapies that could make existing cancer treatments more effective, and potentially less toxic, for patients.”

Researchers believe the metals help tumour cells survive by increasing cellular stress responses linked to harmful molecules known as reactive oxygen species.

This appears to protect cancer cells from the damage normally caused by chemotherapy.

The team says the work could eventually lead to combination therapies in which chemotherapy is paired with metal-removal treatment to improve outcomes for patients and potentially reduce chemotherapy side effects by allowing lower drug doses to be used.

The researchers point out the findings could also have implications beyond lung cancer, as metal build-up has been reported in several other cancer types.

Article: Multi-metal cooperation drives chemoresistance in lung cancer and is reversed by the membrane-permeable chelator MiADMSA

Source: Durham University