Plate Nº 69 · recorded September 30, 2026
Health & Medicine ResearchReported finding
Lung Cancers Evade KRAS Drugs by Switching Cell Type
MIT mouse models show lung adenocarcinomas can resist KRAS inhibitors by transforming into squamous tumors and shutting off KRAS signaling, rather than mutating the drug target.
By Elena Vasquez4 min read747 words
In brief
- About 25% of lung adenocarcinomas carry KRAS mutations, and tumors almost always develop resistance to FDA-approved KRAS-G12C inhibitors.
- In MIT mouse models, loss of the Nkx2-1 gene or overactivity of transcription factors DeltaNp63 and SOX2 allowed lung tumors to transform from adenocarcinoma into squamous cell carcinoma under KRAS inhibition.
- Transformed tumors shut off KRAS signaling rather than acquiring resistance mutations, suggesting alternative growth pathways that could become new drug targets; the study appears in Nature Genetics (2026).
Some lung tumors can resist KRAS-inhibiting drugs not by mutating the drug's target, but by transforming into a different type of cancer altogether, according to a new MIT study published in Nature Genetics.
The finding matters because drug resistance undermines one of the newer tools in lung cancer treatment. About 25% of lung adenocarcinomas — the most common form of non-small cell lung cancer — carry mutations in a gene called KRAS, which drives uncontrolled cell growth. In recent years, the FDA has approved two KRAS inhibitors, both targeting a specific mutation called KRAS-G12C. Doctors prescribe these drugs only after other treatments have failed, usually in patients whose cancer has spread beyond the lungs.
The drugs work in roughly 35% of patients who receive them. But even when they do, tumors almost always find a way around them.
Two ways to fight back
Typically, resistance emerges through a straightforward arms race. Cancer cells acquire new mutations that prevent the drug from binding to KRAS, or they churn out extra copies of the KRAS gene to simply overpower the inhibitor. Both strategies reactivate the MAP kinase signaling pathway — the molecular cascade that KRAS normally switches on to stimulate cell growth.
"Resistance to targeted therapies is a very serious problem," says Carrie Rodriguez, an MIT graduate student and one of the lead authors of the study. "Sometimes these KRAS inhibitors can hold cancers at bay, but most cases do end up relapsing."
The MIT team, led by senior author Tyler Jacks, the David H. Koch Professor of Biology and a member of MIT's Koch Institute for Integrative Cancer Research, modeled a different escape route. Nicolas Mathey-Andrews, who earned his doctorate in 2025, is also a lead author.
A clue came from a 2021 study at Dana-Farber Cancer Institute. Researchers there analyzed tumors from 17 non-small cell lung cancer patients treated with KRAS-G12C inhibitors and found secondary resistance mutations in most of them. But in two patients, something stranger happened: their tumors had transformed from adenocarcinomas into squamous cell carcinomas, without any obvious resistance mutations.
Both tumor types are classified as non-small cell lung cancers, but they are thought to arise from different cells and carry different genetic profiles. Adenocarcinomas often originate from surfactant-producing cells lining the lungs, while squamous cell carcinomas arise from cells lining the central airways. KRAS mutations appear far more frequently in adenocarcinomas.
Rebuilding the transition in mice
To study what drives this transformation, the MIT researchers engineered mice with lung tumors carrying the KRAS-G12C mutation and treated them with a KRAS inhibitor. Tumors that lost a gene called Nkx2-1 — which normally helps lung cells maintain their identity as alveolar epithelial cells — proved able to make the adeno-to-squamous switch under drug treatment.
Two transcription factors, proteins that switch genes on and off, also played roles. DeltaNp63, which is overactive in many squamous cell carcinomas, made the transition more likely. SOX2 also stimulated the shift, although it could not trigger the transition on its own.
Crucially, tumors that completed this transformation did not acquire the mutations that usually boost KRAS activity in adenocarcinomas. Instead, they shut KRAS signaling off completely — and, the researchers hypothesize, switched on alternative signaling pathways that keep them growing. Identifying those pathways could reveal targets for new drugs that prevent or overcome this form of resistance.
"There seem to be several different routes where you can get to squamous transformation, either through loss of lung-lineage-defining transcription factors or overexpression of these squamous master regulators, SOX2 or DeltaNp63," Rodriguez says. "Those resistant squamous tumors no longer respond to KRAS inhibition because they shut off the signaling or at least dampen it significantly."
"The main takeaway is that there seem to be different routes of resistance to KRAS inhibitors, and so we need to be thinking about how we can address this," she adds.
The results come from mouse models, so the picture in human patients may prove more complicated. The researchers are now examining what happens to tumor cells as they shift into a squamous state, hunting for weaknesses that new drugs could exploit.
"Fundamentally, this is a transition that's poorly understood, and we were happy to see that we were able to model it," Mathey-Andrews says. "Future directions that have an eye toward translation will utilize those models to understand the process and conditions by which histologic transformation occurs, and then also nominate potential targets downstream."
via Medical Xpress (Source)
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