New understanding of lung cancer cells’ ‘memories’ suggests novel treatment approach

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A new understanding of the “memory” of lung cancer cells offers a new strategy for improving treatment, Memorial Sloan Kettering Cancer Center (MSK) researchers have found.

Research from the lab of cancer biologist Tuomas Tammela, MD, PhD shows that some lung cancer cells retain a “memory” of the healthy cells from which they came -; An emerging type of lung cancer called KRAS inhibition may be used to treat it.

The study specifically looked at lung adenocarcinoma, a type of non-small cell lung cancer that is the most common type of lung cancer in the United States and accounts for 7% of all cancer deaths. These cancers are often driven by mutations KRAS Gene

For a long time, cancer-driven KRAS proteins were considered ‘incurable’, but within the past few years, the US Food and Drug Administration has approved the first KRAS inhibitor, along with several others, in clinical trials. But they don’t work for everyone, and most patients’ cancers eventually acquire drug resistance and come back.”

Zhuxuan “Zoe” Li, study co-first author, is a doctoral student in the Tamela Lab at the Sloan Kettering Institute at MSK

Group search -; Co-led by Postdoctoral Fellow Xueqian Zhuang, PhD -; sheds important light on lung cancer cells that survive after treatment with a KRAS inhibitor. Importantly, they suggest that treating these cells in addition to treatment with KRAS inhibitors may help prevent recurrence. The study was recently published Cancer discoveryA leading journal for biological insights with important implications for clinical care.

Stem cells with a day job

To discover MSK and understand its effects, it is helpful to know a little lung biology.

Within the lungs, oxygen is absorbed and carbon dioxide is exhaled through air sacs called alveoli. The lining of the alveoli is made up of two distinct types of cells -; Alveolar type 1 (AT1) and alveolar type 2 (AT2).

And while they’re named similarly, these two cells couldn’t be more different.

AT1 cells are long and thin, with a large surface area to facilitate gas exchange between the lungs and the bloodstream.

Meanwhile, AT2 cells play a caring role, secreting compounds important to lung health and function, as well as helping to maintain and repair the lungs by dividing to produce replacement AT1 cells.

“You can think of them as stem cells with a day job,” Dr. Tamela says.

The big problem comes when lung cancer cells -; which normally develop from AT2 cells -; AT1 cells take on some of the “remembered” properties that AT2 cells differentiate when fulfilling their role as stem cells. Scientists call these cancer cells “AT1-like” cells.

Knockdown of AT1-like cells improves the KRAS immune response

In healthy cells, KRAS Plays an important role in regulating cell growth and division. But when the gene is mutated, it can cause runaway cell proliferation.

KRAS inhibitors can stop this explosive growth, greatly shrinking tumors, but they still leave behind pockets of cancer cells that are insensitive to the drug and that give the cancer a chance to develop new mutations to resist the drug’s effects.

The research team studied these residual cancer cells to uncover this resistance mechanism using genetically engineered mouse models, mice implanted with patient-derived tumors, and tumor samples from patients.

They discovered that the cancer cells that remained after treatment were these AT1-like cells. They also found that these cells have the ability to reactivate runaway cancer growth.

“Importantly, we found that if you get rid of these AT1-like cells, it greatly improves treatment response to KRAS inhibitors,” Dr. Tamela says.

Eliminating those cells is relatively easy in experimental models, but doing so in the clinic will require more research.

“We actually live in a very exciting time with excellent pharmacology,” Dr. Tamela says. “We can engineer molecules to bind to a specific cell type and kill them -; This is how CAR T cell therapy and antibody drug conjugates work.

“Now that we’ve done these proof-of-concept experiments, the next step is to find surface proteins that are unique to these AT1-like cells and then develop a therapeutic that can bind to them and kill them,” he said. added ..

Only in places like MSK

Collaboration with other labs was essential for the research, Dr. Tamela says.

“This is the type of research that can really only happen at a place like MSK,” he says. “We had really important collaborations with other labs at MSK that shared animal models and patient samples integral to the study, and we worked closely with several key facilities at MSK -; Antitumor Assessment Core, Integrated Genomics Operations, Flow Cytometry Core, and Molecular Cytology Core.”

MSK investigators Scott Lowe, PhD, and Charles Rudin, MD, PhD, were lead contributors, Drs. Note the tamales.

“And the study would not have been possible without Zoe’s dedication and the model system and early insights developed by Dr. Zhuang,” he added.


Journal Reference:

Lee, Z., etc. (2023). Alveolar differentiation is inhibited by KRAS inhibition in lung adenocarcinoma. Cancer discovery.

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