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New drugs could also be deployed against lung and pancreatic cancers

A new anti-cancer drug may be effective against a wider range of cancers than previously thought, according to a new paper published in Nature Medicine.

Using a mouse model and samples taken from cancer patients, a team from the Technical University of Munich (TUM) has shown that a new class of drugs known as SHP2 inhibitors is also effective against aggressive, hard-to-treat tumours such as lung and pancreatic cancers.

Clinical trials currently underway had previously excluded patients with these cancers.

Lung and pancreatic cancer are collectively referred to as KRAS tumours, as they share the same genetic error.

This error means that the KRAS protein, involved in, among other things, cell division, no longer works properly and is always active.

As a result, the cells divide out of control, leading to tumour formation.

KRAS tumours make up about a third of all tumours in humans.

The problem, however, is that the KRAS protein is also active and plays a crucial role in healthy cells, so that simply deactivating it with drugs is not an option.

New weapon against KRAS tumours

Prof. Hana Algül, Mildred Scheel Professor of Tumour Metabolism and Head of Gastrointestinal Oncology at Medizinische Klinik II at University Hospital rechts der Isar, and his team are therefore on the hunt for alternative points of attack.

"It had previously been thought that the KRAS mutation exerted such severe effects that using other avenues of attack would be doomed to failure," he explains. In their new study, however, the researchers prove that this is not the case.

They show that, contrary to what experts had previously assumed, the regulatory protein SHP2 is a suitable drug target even in KRAS tumours, and that recently developed SHP2 inhibitors are effective against these tumours.

SHP2 protein is essential for tumour growth

One strand of their work involves mice with a defective KRAS protein.

When the team additionally removed the SHP2 protein from the mice, they no longer developed tumours.

With these results, the research team was able to prove that SHP2 is essential for tumour formation and that SHP2 might also be a key drug target in aggressive KRAS tumours.

The results were confirmed when they used recently developed SHP2 inhibitors in their mouse model.

When the mice were given an SHP2 inhibitor, existing tumours grew more slowly and were easier to control.

Combination therapy helps fight resistance

The results could also solve another problem which arises when treating KRAS tumour: they frequently develop drug resistance.

The team tested the new drug in combination with MEK inhibitors, a class of drugs which are already used therapeutically.

"These drugs are effective, but many patients quickly develop resistant cancer cells," explains Katrin Ciecielski, co-author of the paper.

The study found that the new SHP2 inhibitors cause resistant cancer cells to revert to being susceptible to the old MEK inhibitors.

A combination of these two drugs could therefore offer a new approach for treating drug-resistant tumours, suggests Hana Algül.

"We have shown that, both on its own and in combination with other drugs, this new class of drug may one day be able to help cancer patients. This could be life-extending for many patients," says Algül.

He thus recommends that clinical trials currently underway should now accept patients with aggressive KRAS tumours.

He and his team will soon be applying their findings in their own clinical trial.

Source: Technical University of Munich

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