About 20% of adenocarcinomas of the lung are marked by alterations in a cell signaling pathway called KEAP1/NRF2. Now scientists in Australia have learned that these tumors—which are particularly aggressive and occur most commonly in women and young people—may respond well to immuno-oncology treatments.
What’s more, the team identified a “breadcrumb” that these aggressive tumors leave in the blood that they believe could be used to identify patients most likely to respond to drugs that inhibit the immune checkpoints PD-1 and CTLA-4. The marker is also left by adenocarcinomas with abnormalities in another pathway called PI3K. They published their findings in the journal Cell Metabolism.
The researchers, from the Bio21 Institute at University of Melbourne, used preclinical models to identify the biomarkers of KEAP1/NRF2 and PI3K. Their research revealed that mutations in the pathways cause nonstop cell signaling that leads to the development of lung adenocarcinomas, they reported.
They also showed in the models that anti-PD-1 and anti-CTLA-4 drugs cause lung tumors with those abnormalities to shrink. "This is extremely important because these tumors are chemotherapy and radiotherapy resistant, meaning there are effectively no current treatments for these patients," said co-author Sarah Best in a statement.
Bristol-Myers Squibb’s CTLA-4 inhibitor Yervoy and PD-1 inhibitor Opdivo are among the drugs that are approved to treat some lung cancer patients, as is Merck’s PD-1 blocker Keytruda. But these therapies don’t work in all patients, and several research projects are underway to try to improve their utility across patient populations.
For example, scientists at the Francis Crick Institute discovered last year that targeting Ras mutations along with immune checkpoints seems to make checkpoint inhibitors more effective. A team of French researchers found that if they depleted white blood cells known as neutrophils that congregate around lung cancers, they could make the tumors more sensitive to PD-1 blockers in mice.
The Australian researchers believe the molecular signatures they discovered for KEAP1/NRF2 and PI3K mutations could be used not only to identify likely responders to checkpoint inhibitors, but also to develop a blood test for early detection of aggressive lung cancer. They hope to do additional analyses using human samples.