MIT researchers have found that lung tumor cells can become resistant to KRAS inhibitors by undergoing a transformation from adenocarcinoma to squamous cell carcinoma.
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Scientific Frontline: Extended "At a Glance" Summary: Mechanisms of KRAS Inhibitor Resistance in Lung Cancer
The Core Concept: Lung cancer cells can develop resistance to KRAS-inhibiting drugs either by amplifying the KRAS gene to reactivate its signaling or by transforming their cellular identity from adenocarcinoma to squamous cell carcinoma.
Key Distinction/Mechanism: Unlike typical resistance where a tumor mutates to block a drug or simply overpowers it with more of the targeted protein, the lineage transformation mechanism involves the tumor cells fundamentally changing their type. This adeno-to-squamous transition allows the cancer to shut off KRAS signaling entirely and rely on alternative, currently unidentified pathways for continued growth.
Major Frameworks/Components:
- KRAS-G12C Mutation: A specific gene mutation driving uncontrolled cell growth, targeted by two FDA-approved inhibitors.
- Adeno-to-Squamous Transition: The tissue transformation process where lung adenocarcinomas (originating from surfactant-producing cells) transition into squamous cell carcinomas (originating from central airway cells).
- Nkx2-1: A transcription factor whose loss facilitates the transition from adenocarcinoma to squamous cell carcinoma.
- DeltaNp63 and SOX2: Transcription factors that, when overactive, stimulate the transformation to the squamous state.
- MAP Kinase Pathway: A cellular signaling pathway typically triggered by KRAS that stimulates cell growth.
Branch of Science: Oncology, Molecular Genetics, Molecular Biology, Cell Biology.
Future Application: Understanding the specific pathways activated during the adeno-to-squamous transition could reveal new therapeutic targets, leading to drugs that prevent or treat this form of resistance.
Why It Matters: Targeted therapies like KRAS inhibitors are initially effective for about 35 percent of patients, but relapse due to resistance is common. Identifying the exact mechanisms of resistance is critical for developing more durable and effective combination treatments for non-small cell lung cancer.
About 25 percent of lung adenocarcinomas have mutations of the KRAS gene, which drives uncontrolled cell growth. In recent years, the FDA has approved two KRAS inhibitors to treat patients with KRAS mutations. While these drugs can work well initially, tumors almost always develop resistance to them.
Resistance usually emerges because cells reactivate KRAS activity through mutations that prevent drug binding or by increasing KRAS expression, which overpowers the effects of the inhibitor. However, in a new study, MIT researchers modeled an alternative mechanism that cancer cells can use to become resistant to KRAS inhibition.
The researchers found that in some cases, lung tumors undergo a transformation from adenocarcinoma to squamous cell carcinoma. Both of these tumor types are commonly found in the lungs, but they are thought to arise from different cells and have different genetic profiles.
When this transition occurs, tumor cells no longer require KRAS and appear to turn on alternative signaling pathways that help them continue to grow. Ongoing work to identify those pathways may reveal targets for new drugs that could help prevent resistance to KRAS inhibitors.
“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,” says Carrie Rodriguez, an MIT graduate student and one of the lead authors of the paper.
Nicolas Mathey-Andrews, PhD ’25, is also a lead author of the study, which appears today in the journal Nature Genetics. The paper’s senior author is Tyler Jacks, the David H. Koch Professor of Biology and a member of MIT’s Koch Institute for Integrative Cancer Research.
Tissue Transformation
Both FDA-approved KRAS inhibitors target a mutation called KRAS G12C. These drugs are approved only for use in patients whose tumors have failed to respond to other drugs, and these patients usually have cancer that has spread beyond the lungs.
KRAS inhibitors are effective in about 35 percent of the patients who receive them. However, in those cases, the tumors almost always end up becoming resistant by generating additional copies of the KRAS gene or finding other ways to turn on the MAP kinase signaling pathway, which is usually triggered by KRAS and stimulates cell growth.
“Resistance to targeted therapies is a very serious problem,” Rodriguez says. “Sometimes these KRAS inhibitors can hold cancers at bay, but most cases do end up relapsing.”
A 2021 study from researchers at the Dana-Farber Cancer Institute, which analyzed tumors from seventeen patients with non-small cell lung cancer treated with KRAS G12C inhibition, identified secondary resistance mutations in a majority of patients. In two of these patients, however, the researchers found that tumors transformed from adenocarcinomas to squamous cell carcinomas but did not harbor obvious resistance mutations.
Both adenocarcinomas and squamous cell carcinomas are classified as non-small cell lung cancers (NSCLCs), which are the most common type of primary lung cancer. Adenocarcinomas, the most common type of NSCLC, often originate from the surfactant-producing cells that line the lungs, while squamous cell carcinomas originate in the cells that line the central airways of the lungs.
Mutations of the KRAS gene are found much more frequently in adenocarcinomas than in squamous cell carcinomas.
In this study, the researchers set out to model the factors that might drive the transition from adenocarcinomas to squamous cell carcinomas. To do that, they engineered a mouse model of lung cancer to express the mutation targeted by the FDA-approved KRAS inhibitors.
Following treatment with a KRAS G12C inhibitor, tumors with a genetic loss of Nkx2-1, which normally helps maintain alveolar epithelial identity, were able to undergo an adeno-to-squamous transition. Turning on a transcription factor called DeltaNp63, which is overactive in many squamous cell carcinomas, also made this transition more likely. Another transcription factor, known as SOX2, also helped stimulate the transition, but the SOX2 gene could not initiate the transition on its own.
Paths to Resistance
Tumors that underwent these tissue transformations did not acquire the mutations that typically boost KRAS expression in adenocarcinomas. Instead, KRAS signaling was shut off. The researchers hypothesize that these cells may turn on another signaling pathway that helps them continue growing.
“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. Those resistant squamous tumors no longer respond to KRAS inhibition because they shut off the signaling or at least dampen it significantly,” Rodriguez says.
The researchers are now further exploring what happens to tumor cells as they transition to a squamous state, in the hope of identifying vulnerabilities that could be targeted with new drugs.
“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.”
Funding: The research was funded in part by the Koch Institute Support (core) Grant from the National Cancer Institute, a Ruth Kirschstein National Service Research Award, the National Institute of General Medical Sciences, and the Ludwig Center at MIT.
Published in journal: Nature Genetics
Title: Lineage identity governs oncogene dependence in mouse NSCLC models of KRAS inhibitor resistance
Authors: Nicolas Mathey-Andrews, Carrie L. Rodriguez, Bing Shui, Agata L. Patriotis, William M. Rideout III, Victor Z. Chen, Ileana Murazzi, Phaedra Ghazi, Milton R. Cornwall-Brady, Manyuan Liu, Morgan G. Heileman, Marianna Trakala, Carla P. Concepcion-Crisol, Dian Yang, and Tyler Jacks
Source/Credit: Massachusetts Institute of Technology | Anne Trafton
Edited by: Scientific Frontline
Reference Number: ongy093026_01
