Faults in a gene called Ras are caused by smoking and are found in nearly half of all NSCLC patients, especially those with aggressive cancers.
Ras has been considered ‘undruggable’ because of its unique, intricate structure.
Scientists at Cancer Research UK’s London Research Institute have now screened lung cancer cells for unique weaknesses associated with the faulty Ras gene, and have shown that these cells are dependent on another gene, GATA2.
By studying GATA2’s function, they revealed that it acts through two pathways – and drugs are already in use that can disrupt these pathways.
The Cancer Research UK scientists showed that by blocking the cell’s proteasome – the part of a cell responsible for breaking down proteins – and a protein called Rho kinase, they can stop the activity of GATA2. This in turn stops the growth of tumours with faulty Ras genes.
Bortezomib (Velcade), a drug for malignant myeloma, targets the proteasome. And a drug called Fasudil, which is used to treat a vascular condition affecting the heart called pulmonary hypertension, blocks the activity of Rho kinase.
The researchers used this combination of drugs to treat mice with NSCLC caused by faulty Ras genes – the type of lung cancer caused by smoking. They compared the organs before and after treatment and found the drugs had reduced the proportion of the lungs covered by tumours by around 99 per cent.
Dr Julian Downward, lead author from Cancer Research UK’s London Research Institute, said: “The results we saw in our initial studies were extremely promising. It’s very unusual to see such a striking effect – an organ affected by cancer almost completely cleared of the disease.
“It’s too early to say whether this combination of drugs will be effective in patients with lung cancer but plans are underway already to test this theory in a clinical trial.
“If the trial is successful, it will be an extremely exciting step forward in the treatment of lung cancer, and potentially other types of cancer too.
“Ras is one of the most important genes in cancer, and when it goes wrong it can cause extremely aggressive cancers. Nearly a quarter of all cases of cancer are driven by faulty Ras. And in some types of cancer – notably pancreatic cancer – it’s more like nine out of 10 cases.
“So far we’ve just studied mice with lung cancer caused by faulty Ras. But by targeting the biology behind Ras, this combination of drugs holds the potential to treat a wider range of cancers.”
Professor Michael Seckl, Cancer Research UK’s lung cancer clinician based at Imperial College London, said: “Lung cancer kills more people in the UK than any other type of cancer, accounting for around 35,000 deaths each year.
“There are so few effective lung cancer treatments available at the moment, so it’s really encouraging to hear that existing drugs may provide the answer.”
Dr Julie Sharp, senior science information manager at Cancer Research UK, said: “This study is exciting because it suggests that drugs already in use could treat not only this deadly cancer, but other hard-to-treat cancers like pancreatic cancer.
“Cancer Research UK has boosted its research on these cancers in the past few years, so it’s really encouraging to see our scientists making important advances in understanding the biology of cancer. We can immediately build on these results and hope they will lead to a huge step forward in treating the disease.”
For media enquiries, please contact the Cancer Research UK press office on 020 3469 8300 or, out of hours, 07050 264 059.
The GATA2 transcriptional network is requisite for Ras oncogene-driven non-small cell lung cancer. Kumar et al. Cell (2012), doi:10.1016/j.cell.2012.02.059.
Notes to editors
The research was funded by Cancer Research UK and the European Union Framework Programme 7 “LUNGTARGET” consortium, with additional funding from the Human Frontier Science Program and European Molecular Biology Organisation.
Dr Downward is also based at The Institute of Cancer Research.