The study, published in BMC Cancer, focused on the GOT1 tumor model, a xenograft derived from a small intestinal neuroendocrine tumor, one of the most common forms of gastroenteropancreatic neuroendocrine neoplasia. Tumor-bearing BALB/c nude mice received a single non-curative intravenous injection of 15 MBq of [177Lu]Lu-DOTATATE, while control animals received saline. The dose was deliberately chosen to mimic the sub-curative situation seen in many patients, where treatment slows tumor growth but does not eliminate the disease. Tumors were harvested at two time points, one day and thirteen days after treatment, capturing both the immediate molecular response to radiation damage and the later phase in which surviving tumor cells reorganize and begin to regrow.

To follow tumor behavior over time, the researchers monitored tumor volumes with magnetic resonance imaging using rapid acquisition with relaxation enhancement sequences. The imaging confirmed what the team expected: treatment produced a transient reduction in tumor volume, followed by regrowth during the second week. This two-phase pattern gave the investigators a natural framework for interpreting their molecular data, allowing them to distinguish proteins involved in the acute radiation response from those associated with tumor recovery and adaptation.

The core of the study was an unbiased proteomic survey. Using liquid chromatography tandem mass spectrometry combined with tandem mass tag labeling, a technique that allows many samples to be quantified simultaneously and compared with high precision, the team measured the abundance of thousands of proteins in treated and control tumors. In total, 3861 proteins were quantified, and 155 of them showed significantly altered expression after treatment, using a stringent threshold of at least a 1.5-fold change in abundance with a p-value below 0.01 as determined by Welch’s t-test. This is a substantial molecular footprint, and it demonstrates that even a single, non-curative dose of radiolabeled somatostatin analog triggers coordinated changes across broad sectors of the tumor proteome.

Functional enrichment analysis based on Gene Ontology annotations revealed that the affected proteins clustered around several major themes. Cytoskeletal organization was prominently represented, suggesting that the treatment disrupts the structural machinery that tumor cells use to maintain shape, divide, and migrate. Oxidative stress response proteins were also altered, which is consistent with the fundamental mechanism of radiation damage: ionizing radiation generates reactive oxygen species that overwhelm cellular antioxidant defenses and damage DNA, membranes, and proteins. Changes in proteins related to protein metabolism further indicated that the tumors were reworking their synthesis, folding, and degradation systems in response to the insult.

Perhaps the most clinically intriguing results came from pathway analysis performed with Ingenuity Pathway Analysis software. The analysis identified inhibition of several signaling pathways linked to cell migration and invasiveness, including RhoA, Rac, integrin, and CXCR4 signaling. These pathways are central to how cancer cells move through tissue, invade surrounding structures, and seed metastases. Their suppression after treatment suggests that [177Lu]Lu-DOTATATE may not only kill tumor cells directly but also temporarily strip surviving cells of their invasive capabilities, a potentially underappreciated component of the therapy’s anti-tumor effect.

The upstream regulator analysis added another layer of insight, particularly regarding the regrowth phase thirteen days after treatment. At that time point, the data suggested activation of RABL6, a protein implicated in cell cycle regulation and tumor biology, alongside inhibition of p53 signaling. The p53 protein is often described as the guardian of the genome because it responds to DNA damage by halting cell division or triggering cell death. Its apparent inhibition during regrowth raises the possibility that surviving tumor cells dampen this critical checkpoint as they recover from radiation injury, allowing damaged cells that should have been eliminated to persist and proliferate.

The proteomic data also revealed alterations in proteins related to endoplasmic reticulum stress and the ubiquitin-proteasome system. The endoplasmic reticulum is the cellular compartment where newly made proteins are folded and quality-controlled, and when radiation damage disrupts protein folding on a large scale, cells activate the unfolded protein response to cope with the backlog. The ubiquitin-proteasome system, meanwhile, serves as the cell’s waste disposal machinery, degrading damaged or misfolded proteins. Changes in both systems indicate that the treated tumors were under significant proteotoxic stress, struggling to maintain protein homeostasis in the aftermath of irradiation. Selected findings from the mass spectrometry analysis were independently validated using enzyme-linked immunosorbent assays, strengthening confidence in the key results.

Taken together, these findings suggest rational combination strategies. If p53 signaling is inhibited during regrowth, pairing [177Lu]Lu-DOTATATE with agents that restore or enhance p53 function could prevent surviving cells from evading the checkpoint that would otherwise eliminate them. Similarly, if tumors rely on endoplasmic reticulum stress responses to survive treatment, drugs that push this stress past the point of recovery, such as proteasome inhibitors or agents that block the unfolded protein response, could convert a transient tumor shrinkage into a durable regression. The suppression of migration and invasion pathways also raises the possibility of combining the radionuclide therapy with inhibitors of RhoA, Rac, integrin, or CXCR4 signaling to lock tumor cells in a less aggressive state.

The authors emphasize that their work was conducted in a preclinical xenograft model with a deliberately non-curative dose, so translating these observations into clinical practice will require further validation in additional models and ultimately in patient tumors. Nevertheless, the study provides one of the most comprehensive proteomic portraits to date of how neuroendocrine tumors respond molecularly to peptide receptor radionuclide therapy. By identifying the specific pathways that tumors activate to survive and regrow, the research transforms a long-standing clinical frustration, the gap between tumor response and cure, into a set of concrete molecular targets. For a disease category in which treatment options have historically been limited, that shift from observation to actionable biology may prove to be the study’s most important contribution.

Subject of Research: Proteomic changes in small intestinal neuroendocrine tumor xenografts after lutetium-177 DOTATATE peptide receptor radionuclide therapy

Article Title: Profiling proteomic responses in small intestinal neuroendocrine tumor GOT1 after [177Lu]Lu-DOTATATE therapy

Article References: Spetz, J. K., Montelius, M. E., Berger, E., Johansson, J. A., Rassol, N., Ljungberg, M., & Forssell-Aronsson, E. B. (2026). Profiling proteomic responses in small intestinal neuroendocrine tumor GOT1 after [177Lu]Lu-DOTATATE therapy. BMC Cancer, 26(1), Article 1111. https://doi.org/10.1186/s12885-026-16975-3

Image Credits: AI Generated

DOI: 10.1186/s12885-026-16975-3

Keywords: neuroendocrine tumors, peptide receptor radionuclide therapy, lutetium-177, DOTATATE, proteomics, mass spectrometry, p53 signaling, endoplasmic reticulum stress, RhoA signaling, CXCR4, GOT1 xenograft, radiation biology