From Memorial Sloan Kettering Cancer Center

Summary

Aggressive lung cancer and a new target: An MSK team has found that a particular subset of lung adenocarcinomas is aggressive due to a combination of two mutations that allow them to block ferroptosis, a type of cell death.

Targeted therapies are currently available for about one-third of people with lung adenocarcinoma, the most common kind of lung cancer. These drugs inhibit cancer cells by thwarting the molecular changes that drive them to grow while largely sparing healthy tissues. But for the other two-thirds of people with this type of cancer, there are fewer treatment options.

New findings reported for aggressive lung cancer

A team from Memorial Sloan Kettering is reporting new findings about a particularly aggressive subset of lung adenocarcinomas that are driven by two mutations that frequently occur together, in genes called KEAP1 and STK11. The molecular changes characteristic of these tumors were surprising to the investigators who discovered them: they block a type of cell death called ferroptosis. Cancers with these changes require this blockade to stay alive and grow. The study was published December 1, 2020, in Cell Reports.

Ferroptosis is a type of programmed cell death that is dependent on iron. Ferroptosis was discovered less than a decade ago, but it has already emerged as an important target for cancer therapies as well as drug treatments for other diseases. When ferroptosis fails to occur when it should, cells can grow uncontrollably.

“We really didn’t know what particular vulnerabilities we would find in these cancer cells,” says MSK physician-scientist Charles Rudin, Chief of the Thoracic Oncology Service, Co-Director of the Fiona and Stanley Druckenmiller Center for Lung Cancer Research, and the paper’s senior author. “But all of the work we report in this study pointed toward ferroptosis as a key player.”

Two Mutations Working Together

The genetic change that allows the cancer cells to block ferroptosis is called a co-mutation: alterations in two genes called STK11 and KEAP1 work together to create an environment in which tumor cells are able to grow even when they are receiving signals that would otherwise induce cell death. The combination of mutations in these two genes is found in more than 10% of lung adenocarcinomas, so a drug that could successfully target this alteration would have a meaningful impact.

MSK biostatistician Ronglai Shen was the first to discover that the STK11/KEAP1 co-mutation is often found in lung adenocarcinomas that are very aggressive and hard to treat. She made the discovery when doing an analysis of lung cancer using data from MSK-IMPACT^TM, a test that looks for hundreds of mutations in tumors at the same time. Dr. Shen is a co-author on the new study.

The connection to ferroptosis was unexpected. “Our findings suggest that targeting certain proteins that play a role in the regulation of ferroptosis could lead to new treatments for this cancer,” Dr. Rudin says.