EGFR. ALK. BRAF. MET. NTRK. RET. ROS1. This may seem like what you see when you dump a box of Scrabble tiles on a table, but these letter combinations are actually the names of genes that — when mutated — drive the formation, growth, and spread of lung cancer.

In aggregate, mutations in these seven genes cause about one-third of all non-small cell lung cancers. And each of them has at least one drug designed to counteract them that’s been approved by the US Food and Drug Administration. For patients who are matched with one of these drugs, treatment tends to be much more effective than it is with chemotherapy, which kills not just cancer but all fast-growing cells. Additionally, targeted drugs usually have fewer side effects than other forms of treatment.

“Our goal is always to find the best treatment for every patient,” says Memorial Sloan Kettering medical oncologist Helena Yu, who specializes in evaluating targeted therapies for lung cancer. “But you don’t know what the best treatment is until you look at all the options, and you won’t know all the options until you do molecular testing.”

A History of Developing Molecular Tests

Nearly two decades ago — when the first drugs for EGFR mutations were being evaluated — researchers at MSK recognized that targeted therapy would be an especially important approach for people with lung cancer. This was because the drugs worked extremely well in a subset of patients. Also, many people stood to benefit because lung cancer is so common. Targeted drugs work by zeroing in on the activities of mutated proteins in cancer cells and shutting down the cells’ growth, mostly sparing healthy cells.

MSK researchers also understood how vital it was to examine tumor tissue and determine whether it contained the mutations that were being targeted. Studies had shown that EGFR drugs were quite effective in people whose tumors had EGFR mutations. Those whose tumors had other mutations would not benefit. (What happened is not uncommon in cancer drug development — when the trials of drugs targeting EGFR began, investigators didn’t know who would most benefit from them.)

In 2004, MSK was one of the first hospitals in the world to begin regularly testing people with non-small cell lung cancer for EGFR mutations. The development of this clinical test was led by molecular pathologist Marc Ladanyi.

In the years after that test was created, Dr. Ladanyi and his team in MSK’s Molecular Diagnostics Service have continued to roll out new molecular tests, including MSK-IMPACT^TM, which expanded the benefits of molecular testing to all solid tumors. Today, this test can detect alterations in 505 cancer-related genes while requiring only one small piece of tissue. MSK-IMPACT was cleared as a tumor genetic profiling assay by the FDA in 2017. In 2019, MSK began using MSK-ACCESS, a tool that can detect mutations in 129 genes by analyzing just a small amount of blood. MSK-IMPACT and MSK-ACCESS enable doctors to match patients with drugs designed to target their tumors and provide them with many other details about a tumor’s genetics as well.

“When a patient comes to me with newly diagnosed, metastatic lung cancer, the first thing I do is order an MSK-ACCESS test for them,” Dr. Yu says. “We get the results within two weeks, and if their cancer cells contain one of these mutations, we can start them on a targeted therapy right away.” Because MSK-IMPACT requires a tissue sample, it may not be available to patients who received their biopsy and diagnosis at another hospital. But if enough tissue is left over from earlier tests, MSK-IMPACT can be used to confirm the diagnosis and provide further detail. “MSK-IMPACT is still the gold standard for molecular testing,” she adds.

Clinical Trials Lead to New Therapies

As leader of MSK’s Early Drug Development Service, medical oncologist Alexander Drilon has been at the helm of several clinical trials for targeted therapies that are now used to treat lung and other cancers. Recently, he led the clinical trial that resulted in the FDA’s approval of selpercatinib (Retevmo^TM), which treats lung and thyroid cancers driven by a mutation called a RET fusion. Studies showed that among patients who had stopped responding to other drugs, 64% had their tumors shrink when treated with selpercatinib. For those who had never received chemotherapy or another treatment, the response was even higher — 85%.

“As more targeted therapies are developed, tests like MSK-IMPACT that look for many mutations at the same time have become so important,” Dr. Drilon said. “If you run individual tests for each mutation separately, you’ll exhaust the amount of the patient’s tumor tissue that’s available for analysis.”

Selpercatinib and other targeted therapies were initially approved to treat stage IV disease that could not be operated on — cancers that had spread beyond the lungs to other parts of the body. Investigators at MSK are now conducting studies to determine whether they can help people with less-advanced cancers. The drugs may be given before surgery, to shrink tumors and make them easier to remove, or after surgery, to destroy any cancer that may be left behind.

Unfortunately, many people can develop resistance to these drugs, and MSK researchers are now focused on developing new drugs that can take over when one targeted therapy stops working. MSK-ACCESS plays an important role here, too: Doctors can use blood tests to monitor the cancer and determine whether it has acquired additional mutations without having to conduct a surgical or needle biopsy to get another tissue sample.

Advancing the Search for New Drugs and New Targets

MSK investigators are also leading the way in the search for drugs that target mutations in other genes. In September 2020, medical oncologists Bob Li and Piro Lito published results from the first-ever trial for sotorasib, a drug that targets a mutation called KRAS-G12C. This mutation is found in about 10% of non-small cell lung cancers, most often in former or current smokers.

Dr. Li and Dr. Drilon are also conducting a trial to determine whether the drug trastuzumab deruxtecan (Enhertu^®), which was approved for breast cancer in December 2019, is effective in treating lung cancers driven by genetic changes in a gene called HER2.

“You need really good sequencing tests to find all these mutations,” Dr. Drilon says. “As testing becomes cheaper and more and more drugs become available, the medical community needs to move toward a paradigm where every person with lung cancer receives molecular testing.”

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.

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.

CRISPR Helps Create Useful Lab Models

In the current study, first author Corrin Wohlhieter, a graduate student in the lab that’s co-led by Dr. Rudin and Triparna Sen, used the gene editing tool CRISPR — which allows researchers to make very specific changes to the genetic code — to create three types of cells: some of these cells had the gene STK11 knocked out, some had KEAP1 knocked out, and some had both genes knocked out. She then isolated each of the three cell types and studied them in the lab, including in mouse models. By analyzing the cells’ behaviors, she was able to figure out which other genes were activated when STK11 and KEAP1 were lost.

“Lung cancers tend to be very heterogeneous, so if you don’t do these kinds of controlled experiments it’s hard to isolate changes attributable to a particular gene or set of genes,” Dr. Rudin says. “By creating these knockouts, it allows us to really focus on cells with these mutations and to link any behaviors we observe to the presence or absence of these factors.”

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

“Although the current SCD1 inhibitors that we have are not likely to make good drugs,” he explains, “there are many labs at MSK that are actively investigating strategies for targeting ferroptosis in cancer cells.”

Dr. Rudin says he plans to work with other researchers to learn more about these interactions and to look for compounds that could be developed into drugs. “We hope to find drugs that inhibit the pathways in these tumor cells, ultimately developing a targeted therapy strategy for these particularly difficult cancers,” he concludes.

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.

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.O

CRISPR Helps Create Useful Lab Models

In the current study, first author Corrin Wohlhieter, a graduate student in the lab that’s co-led by Dr. Rudin and Triparna Sen, used the gene editing tool CRISPR — which allows researchers to make very specific changes to the genetic code — to create three types of cells: some of these cells had the gene STK11 knocked out, some had KEAP1 knocked out, and some had both genes knocked out. She then isolated each of the three cell types and studied them in the lab, including in mouse models. By analyzing the cells’ behaviors, she was able to figure out which other genes were activated when STK11 and KEAP1 were lost.

“Lung cancers tend to be very heterogeneous, so if you don’t do these kinds of controlled experiments it’s hard to isolate changes attributable to a particular gene or set of genes,” Dr. Rudin says. “By creating these knockouts, it allows us to really focus on cells with these mutations and to link any behaviors we observe to the presence or absence of these factors.”

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

“Although the current SCD1 inhibitors that we have are not likely to make good drugs,” he explains, “there are many labs at MSK that are actively investigating strategies for targeting ferroptosis in cancer cells.”

Dr. Rudin says he plans to work with other researchers to learn more about these interactions and to look for compounds that could be developed into drugs. “We hope to find drugs that inhibit the pathways in these tumor cells, ultimately developing a targeted therapy strategy for these particularly difficult cancers,” he concludes.