Unexpected findings reveal new targets for aggressive forms of lung cancer

Targeted therapies are currently available to about one-third of patients with lung adenocarcinoma, the most common type of lung cancer. These drugs block cancer cells by blocking the molecular changes that cause them to grow, while significantly saving healthy tissue. However, for the other two-thirds of people with this type of cancer, treatment options are limited.

The Memorial Sloan Kettering team is reporting new discoveries about a particularly aggressive subset of lung adenocarcinoma caused by two frequently co-occurring mutations in genes called KEAP1 and STK11.The· Molecular change The characteristics of these tumors were surprising to the researchers who discovered them. They prevent a type of cell death called ferroptosis. Cancers with these changes need this blockade to survive and grow.This study was conducted on December 1, 2020 Cell reports..

Ferroptosis is a type of programmed cell death that depends on iron. Although ferroptosis was discovered within 10 years, it has already emerged as an important target for cancer treatment, as well as drug treatment for other diseases. If ferroptosis should occur but not, cell It can grow out of control.

“I really didn’t know what specific vulnerabilities were found in these cancer cells,” said Fiona and Stanley Druckenmiller, MSK’s physician scientist and director of chest oncology services. Charles Rudin, co-director of the Lung Cancer Research Center, said. Lead author of the treatise. “But all the studies reported in this study were aimed at ferroptosis as a major player.”

Two mutations that work together

The genetic changes that allow cancer cells to block ferroptosis are called comutations. Changes in two genes, called STK11 and KEAP1, work together to create an environment in which tumor cells can grow even when they are receiving signals that would otherwise elicit. Cell death.. The combination of mutations in these two genes is found in more than 10% of lung adenocarcinomas, so drugs that can successfully target this change will have meaningful effects.

MSK biostatistician Ronglai Shen first discovered that STK11 / KEAP1 co-mutations are common in highly aggressive and difficult-to-treat lung adenocarcinomas.She made a discovery when doing an analysis of lung Cancer using data from MSK-IMPACT TM. This is a test that simultaneously looks for hundreds of mutations in a tumor. Dr. Shen is a co-author of a new study.

The relationship with ferroptosis was unexpected. “Our findings suggest that targeting specific proteins that play a role in the regulation of ferroptosis may lead to new therapies for this. cancer“Dr. Rudin says.

CRISPR helps you create useful lab models

In the current study, the lead author, Corrin Wohlhieter, a graduate student in a lab co-led by Dr. Rudin and Triparnasen, used the gene editing tool CRISPR. This allows researchers to make very specific changes to the genetic code. Three types of cells: Some of these cells were knocked out of the gene STK11, some were knocked out of KEAP1, and some were knocked out of both genes. She then isolated each of the three cell types and studied them in a lab that included a mouse model. By analyzing cell behavior, she was able to understand which other genes were activated when STK11 and KEAP1 were lost.

“Lung cancer tends to be very heterogeneous, and without these types of controlled experiments, it is difficult to isolate changes caused by a particular gene or set of genes. gene“By creating these knockouts, we can actually focus on cells with these mutations and correlate the observed behavior with the presence or absence of these factors,” says Dr. Rudin.

The team’s observations helped them get involved in ferroptosis. They found that cells with both STK11 and KEAP1 mutations also had high levels of proteins that were already known to make cells resistant to ferroptosis. Dr. Rudin and his colleagues have identified one of these proteins, called SCD1, as a particularly good target for these tumors.

“While our current SCD1 inhibitors are unlikely to make good drugs, MSK has many laboratories that are actively investigating strategies to target ferroptosis. cancer cell.. “

Dr. Rudin said he plans to work with other researchers to learn more about these interactions and look for compounds that have the potential to develop into drugs. “We want to find drugs that block the pathways of these tumor cells and ultimately develop targeted therapies for these particularly difficult cancers,” he concludes.