MIT study finds two routes by which lung tumors resist a KRAS inhibitor

MIT researchers reported on September 30 that lung tumors in mouse models resisted the KRAS inhibitor sotorasib through distinct routes: some restored growth signaling, while others changed from adenocarcinoma to squamous cell carcinoma. The finding offers a way to investigate a tumor-type change previously observed in patients, but it does not establish a new treatment for people with lung cancer.

The team treated genetically engineered mice with KRAS G12C-driven lung tumors until resistance emerged. In the accessible preprint abstract, the researchers describe an initial response to sotorasib that was rapid but incomplete. Continued treatment produced several forms of resistance. MIT says the work appeared in Nature Genetics on September 30; the accessible study text is a preprint dated July 24, 2025.

How the mouse tumors resisted sotorasib

One route involved renewed activity in the MAPK signaling pathway, which promotes cell growth and is normally driven by KRAS. MIT describes increased copies of the KRAS gene as one way a tumor can overcome inhibition. This route leaves the tumor dependent on growth signaling that the drug was designed to interrupt, even as the cells find ways to restore it.

A different route involved a change in the tumor's tissue identity. Some adenocarcinomas became squamous tumors during treatment. The squamous-transformed tumors in the model showed no evidence of renewed KRAS or MAPK signaling. That distinction matters to the research question: a tumor that grows while dampening that pathway may require a different explanation for its resistance than one that reactivates it.

Carrie Rodriguez, a lead author, said: ‘There seem to be different routes of resistance to KRAS inhibitors, and so we need to be thinking about how we can address this.’ Nicolas Mathey-Andrews was also a lead author, and Tyler Jacks was the study's senior author. The experiments identify conditions associated with resistance in models; they do not show that altering those factors would prevent relapse in patients.

What earlier patient samples showed

A separate, multi-institutional study reported by Dana-Farber Cancer Institute in 2021 found evidence of varied resistance after treatment with adagrasib, another KRAS G12C inhibitor. Its investigators collected samples from 38 patients whose cancers had progressed: 27 had non-small cell lung cancer, 10 had colorectal cancer and one had cancer of the appendix. They identified possible resistance mechanisms in 17 patients; seven of those 17 had more than one possible mechanism.

The Dana-Farber investigators found acquired changes in KRAS, including extra copies of KRAS G12C, as well as changes in other genes, including BRAF and MET. In two patients, lung adenocarcinomas had changed to squamous cell carcinomas. Those observations came before the MIT mouse-model work and provide clinical context for the transformation the MIT team set out to examine. They do not establish how common that change is among all patients treated with KRAS inhibitors.

What the findings leave open

The two patient cases and the mouse experiments answer different questions. The patient samples show that a change in tumor type can occur after KRAS G12C inhibitor treatment. The models let researchers test how changes in cell identity can accompany resistance. The cited evidence does not establish how often the mechanism modeled at MIT occurs in patients, or whether targeting it would improve outcomes.

MIT says its researchers are now examining what happens as tumors move toward a squamous state, hoping to identify pathways and potential drug targets. The published account does not describe a therapy tested in patients to prevent this form of resistance. For now, the finding sharpens the explanation of how resistance can arise: renewed growth signaling and a change in tumor identity are both observed routes, and a treatment strategy for the latter remains an open research question.