A new understanding of lung cancer cells’ “memories” suggests a new strategy for improving treatment, Memorial Sloan Kettering Cancer Center (MSK) researchers have found.
The study looked specifically at lung adenocarcinoma, a type of non-small cell lung cancer that is the most common type of lung cancer in the U.S. and responsible for 7% of all cancer deaths. This cancer is frequently driven by mutations in the KRAS gene.
“For a long time, cancer-driving KRAS proteins were considered ‘undruggable,'” says study co-first author Zhuxuan “Zoe” Li, a doctoral student in the Tammela Lab at MSK’s Sloan Kettering Institute. “Within the last few years, however, the U.S. Food and Drug Administration approved the first KRAS inhibitors, with quite a few more in clinical trials. But they don’t work for everyone, and most patients’ cancers eventually acquire resistance to the drugs and come back.”
The team’s findings—co-led by postdoctoral fellow Xueqian Zhuang, Ph.D.—shed important light on lung cancer cells that linger after treatment with a KRAS inhibitor. Importantly, they suggest that separately targeting these cells alongside treatment with a KRAS inhibitor could help prevent recurrence. The study was recently published in Cancer Discovery, a leading journal for biological insights that have important implications for clinical care.
Stem cells with a day job
To understand the MSK discovery and its implications, it’s helpful to know a little about lung biology.
Within the lungs, oxygen is absorbed and carbon dioxide is released via air sacs called alveoli. The lining of the alveoli is made of two distinct types of cells—alveolar type 1 (AT1) and alveolar type 2 (AT2).
And while they’re similarly named, these two cells couldn’t be more different.
AT1 cells are long and thin, with a large surface to facilitate gas exchange between the lungs and the bloodstream.
AT2 cells, meanwhile, play a caretaking role, secreting compounds that are important for the health and function of the lungs, as well as helping maintain and repair the lungs by dividing to create replacement AT1 cells.
“You can think of them as stem cells with a day job,” Dr. Tammela says.
The big problem comes when lung cancer cells—which typically develop from AT2 cells—take on some “remembered” properties of the AT1 cells that AT2 cells differentiate into when they’re playing their stem cell role. Scientists call these cancer cells “AT1-like” cells.
Eliminating AT1-like cells improves response to KRAS inhibition
In healthy cells, KRAS plays a key role in regulating cell growth and division. But when the gene becomes mutated, it can lead to runaway cell proliferation.
KRAS inhibitors can switch off this explosive growth, greatly diminishing tumors, but they still leave behind pockets of cancer cells that aren’t sensitive to the drug, and that also gives the cancer a chance to develop new mutations to resist the drugs’ effects.
The research team painstakingly studied these residual cancer cells to uncover the mechanisms of this resistance 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 these cells have the capacity to reignite the cancer’s runaway growth.
“Importantly, we found that if you get rid of these AT1-like cells, it greatly improves the treatment response to KRAS inhibitors,” Dr. Tammela says.
Eliminating those cells in experimental models is relatively easy, but doing so in the clinic will require further research.
“We actually live in a very exciting time with fantastic pharmacology,” Dr. Tammela says. “We can engineer molecules to bind to a certain 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 would be 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 adds.
Only at a place like MSK
Collaborations with other labs were essential to the research, Dr. Tammela 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 that were integral to the study, and we worked closely with several of MSK’s core facilities—the Antitumor Assessment Core, Integrated Genomics Operation, Flow Cytometry Core, and Molecular Cytology Core.”
MSK investigators Scott Lowe, Ph.D. and Charles Rudin, MD, Ph.D. were key contributors, Dr. Tammela notes.
“And the study would not have been possible without Zoe’s dedication, and the model systems and initial insights developed by Dr. Zhuang,” he adds.
Additional authors include Chun-Hao Pan, Yan Yan, Rohit Thummalapalli, Stefan Torborg, Anupriya Singhal, Jason Chang, and Rona Yaeger of MSK; Simon Joost, formerly of MSK and now at GC Therapeutics; Eusebio Manchado, formerly of MSK, now at the Novartis Institute for Biomedical Research; Jill Hallin and James Christensen of Mirati Theraputics; and Lukas Dow of Weill Cornell Medicine.
More information: Zhuxuan Li et al, Alveolar differentiation drives resistance to KRAS inhibition in lung adenocarcinoma, Cancer Discovery (2023). DOI: 10.1158/2159-8290.CD-23-0289
![](https://www.nanoappsmedical.com/wp-content/uploads/2017/05/spacer.jpg)
News
The Silent Battle Within: How Your Organs Choose Between Mom and Dad’s Genes
Research reveals that selective expression of maternal or paternal X chromosomes varies by organ, driven by cellular competition. A new study published today (July 26) in Nature Genetics by the Lymphoid Development Group at the MRC [...]
Study identifies genes increasing risk of severe COVID-19
Whether or not a person becomes seriously ill with COVID-19 depends, among other things, on genetic factors. With this in mind, researchers from the University Hospital Bonn (UKB) and the University of Bonn, in [...]
Small regions of the brain can take micro-naps while the rest of the brain is awake and vice versa
Sleep and wake: They're totally distinct states of being that define the boundaries of our daily lives. For years, scientists have measured the difference between these instinctual brain processes by observing brain waves, with [...]
Redefining Consciousness: Small Regions of the Brain Can Take Micro-Naps While the Rest of the Brain Is Awake
The study broadly reveals how fast brain waves, previously overlooked, establish fundamental patterns of sleep and wakefulness. Scientists have developed a new method to analyze sleep and wake states by detecting ultra-fast neuronal activity [...]
AI Reveals Health Secrets Through Facial Temperature Mapping
Researchers have found that different facial temperatures correlate with chronic illnesses like diabetes and high blood pressure, and these can be detected using AI with thermal cameras. They highlight the potential of this technology [...]
Breakthrough in aging research: Blocking IL-11 extends lifespan and improves health in mice
In a recent study published in the journal Nature, a team of researchers used murine models and various pharmacological and genetic approaches to examine whether pro-inflammatory signaling involving interleukin (IL)-11, which activates signaling molecules such [...]
Promise for a universal influenza vaccine: Scientists validate theory using 1918 flu virus
New research led by Oregon Health & Science University reveals a promising approach to developing a universal influenza vaccine—a so-called "one and done" vaccine that confers lifetime immunity against an evolving virus. The study, [...]
New Projects Aim To Pioneer the Future of Neuroscience
One study will investigate the alterations in brain activity at the cellular level caused by psilocybin, the psychoactive substance found in “magic mushrooms.” How do neurons respond to the effects of magic mushrooms? What [...]
Decoding the Decline: Scientific Insights Into Long COVID’s Retreat
Research indicates a significant reduction in long COVID risk, largely due to vaccination and the virus’s evolution. The study analyzes data from over 441,000 veterans, showing lower rates of long COVID among vaccinated individuals compared [...]
Silicon Transformed: A Breakthrough in Laser Nanofabrication
A new method enables precise nanofabrication inside silicon using spatial light modulation and laser pulses, creating advanced nanostructures for potential use in electronics and photonics. Silicon, the cornerstone of modern electronics, photovoltaics, and photonics, [...]
Caught in the actinium: New research could help design better cancer treatments
The element actinium was first discovered at the turn of the 20th century, but even now, nearly 125 years later, researchers still don't have a good grasp on the metal's chemistry. That's because actinium [...]
Innovative Light-Controlled Drugs Could Revolutionize Neuropathic Pain Treatment
A team of researchers from the Institute for Bioengineering of Catalonia (IBEC) has developed light-activated derivatives of the anti-epileptic drug carbamazepine to treat neuropathic pain. Light can be harnessed to target drugs to specific [...]
Green Gold: Turning E-Waste Into a Treasure Trove of Rare Earth Metals
Scientists are developing a process inspired by nature that efficiently recovers europium from old fluorescent lamps. The approach could lead to the long-awaited recycling of rare earth metals. A small molecule that naturally serves [...]
Cambridge Study: AI Chatbots Have an “Empathy Gap,” and It Could Be Dangerous
A new study suggests a framework for “Child Safe AI” in response to recent incidents showing that many children perceive chatbots as quasi-human and reliable. A study has indicated that AI chatbots often exhibit [...]
Nanoparticle-based delivery system could offer treatment for diabetics with rare insulin allergy
Up to 3% of people with diabetes have an allergic reaction to insulin. A team at Forschungszentrum Jülich has now studied a method that could be used to deliver the active substance into the [...]
Nanorobot kills cancer cells in mice with hidden weapon
Researchers at Karolinska Institutet in Sweden have developed nanorobots that kill cancer cells in mice. The robot's weapon is hidden in a nanostructure and is exposed only in the tumor microenvironment, sparing healthy cells. [...]