Statins vs. Metastases: Atorvastatin Slows Down 'Mesenchymal' Lung Cancer

A common "heart" drug, atorvastatin, may also be useful in oncology. A study in Scientific Reports showed that the drug selectively inhibits the growth, migration, and invasion of non-small cell lung cancer (NSCLC) cells with mesenchymal features. The mechanism is the blockade of nuclear activity of YAP/TAZ, key coactivators of the Hippo pathway, through the depletion of the GGPP metabolite in the mevalonate pathway. This effect has almost no effect on "epithelial" cells - it is the phenotype that determines sensitivity to statins.

Background of the study

Non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer mortality, and progress in many molecular subtypes is still modest. The variant with pronounced mesenchymal features (EMT-high) is especially “stubborn”: such tumors metastasize faster, respond worse to standard chemo- and immunotherapy, and are prone to drug resistance after targeted regimens. Biologically, this aggressive phenotype is often associated with increased activity of YAP/TAZ coactivators (Hippo pathway), which include programs for migration, invasion, and survival of tumor cells.

The Hippo-YAP/TAZ pathway is sensitive to mechanical signals and to the state of the cytoskeleton, which in turn “feeds” on the products of the mevalonate pathway - isoprenoids (e.g., GGPP), which are necessary for prenylation of small GTPases (Rho/Rac). When prenylation is impaired, the activity of Rho signaling decreases, and YAP/TAZ enter the nucleus less, weakly triggering their targets. This makes the mevalonate pathway an attractive “indirect” point of attack on YAP/TAZ-dependent tumors.

Statins, HMG-CoA reductase inhibitors, have long been used safely in cardiology, and in preclinical models have shown the ability to deplete the GGPP pool and interfere with those same prenylatable nodes, affecting the migration and proliferation of cancer cells. But clinical observations on the "anti-cancer" effect of statins are contradictory, probably due to the biological heterogeneity of tumors: if sensitivity is indeed determined by phenotype (EMT) and dependence on YAP/TAZ, then "average" analyses blur the signal.

Hence the logic of the current work: not to test statins “in general on NSCLC,” but to focus on the mesenchymal subtype, where YAP/TAZ play a leading role. If it can be shown in such tumors that a statin selectively dampens YAP/TAZ nuclear activity and inhibits invasiveness, this will open a window for repositioning a cheap and well-studied class of drugs as an adjuvant - with biomarker selection of patients (EMT signature, YAP/TAZ targets) and rational combinations with current treatment standards.

What did the scientists do?

• The effect of atorvastatin was compared in several NSCLC cell lines with different epithelial-mesenchymal transition (EMT) features, ranging from "epithelial" to "mesenchymal".
• Viability, migration, invasion, as well as YAP/TAZ localization (nucleus/cytoplasm) and expression of their target genes were measured.
• Additionally, YAP and TAZ siRNA were “switched off” to test how critical the coactivators themselves are for proliferation.
• The anti-metastatic effect was tested in vivo in chicken embryos (CAM model) and in xenotransplantation models in mice.

In the "mesenchymal" circuit, everything came together. Atorvastatin reliably reduced proliferation, migration and invasion in mesenchymal-like cells (vimentin↑, E-cadherin is absent from the membrane), while epithelial lines responded weakly. In parallel, in sensitive cells, YAP/TAZ left the nucleus, their target genes "went out" (for example, SLC2A1/GLUT1, ANKRD1), and double knockdown of YAP+TAZ suppressed growth in all tested lines - that is, the pathway is important for everyone, but statin turns it off more effectively in the mesenchymal subtype.

Briefly about the mechanism

• Statins inhibit HMG-CoA reductase → the synthesis of GGPP, the “attachment” for small GTPases, decreases.
• Without GGPP, Rho signaling, which normally drives YAP/TAZ into the nucleus, works less well.
• Conclusion: phosphorylated YAP/TAZ remain in the cytoplasm and do not turn on growth/movement/apoptosis resistance genes.

Main findings

• Phenotype selectivity: "mesenchymal" NSCLC are significantly more sensitive to atorvastatin than "epithelial" NSCLC.
• YAP/TAZ is a weak spot: their combined suppression by siRNA inhibits the growth of all lines; atorvastatin specifically reduces nuclear localization and activity of YAP/TAZ more strongly in mesenchymal cells.
• An anti-metastatic signal in vivo: in the CAM model, statin reduced cell seeding in embryonic lungs; in the mouse xenograft, there was a trend, but the model was not ideal - the authors emphasize the need for orthotopic testing.
• Heterogeneity even among the “mesenchymal” ones: one of the lines (RERF-LC-MS) responded weaker - probably due to less dependence on YAP/TAZ.

Why is this important?

NSCLC with pronounced EMT is a more aggressive subtype prone to metastases and resistance to therapy. The work hints at repositioning statins as an adjuvant in this group - for example, next to EGFR inhibitors, where YAP activity is associated with drug resistance. At the same time, not all patients need a statin "for cancer": biomarker selection is critical - the YAP/TAZ signature and the EMT phenotype.

How this may affect practice

• Who to look for: patients with NSCLC/YAP-TAZ-high/EMT-high (vimentin↑, E-cadherin↓; YAP/TAZ target transcriptome panels).
• How to use: in combination with the main treatment (targets, chemotherapy, IT) - as an attempt to suppress invasiveness/migration and enhance the response.
• What to monitor: expression of YAP/TAZ targets and dynamics of EMT markers against the background of statin addition.

But let's keep our heads cool

• This is pre- and early in vivo biology: cell models, CAM, xenografts, without full orthotopic confirmation and without clinical outcomes.
• Sensitivity depends on the phenotype; a universal “all-NSCLC” effect should not be expected.
• Dosage/pharmacokinetics of oncologic statin use, drug interactions and risk of myopathy require careful clinical design.

Context in two sentences

YAP/TAZ is one of the key drivers of malignant behavior in many tumors, including NSCLC; its activity is increased specifically in mesenchymal subtypes. It makes sense that where YAP/TAZ is loudest, inhibition of the mevalonate pathway produces a more pronounced antitumor effect - and this is exactly what the work demonstrates.

Summary

Atorvastatin has a compelling mechanistic case against mesenchymal NSCLC: via YAP/TAZ, it not only slows cell growth but also disrupts cell motility and invasion. Now it’s time for orthotopic models and pragmatic clinical trials with biomarker selection to understand who and in what setting this adjuvant strategy really helps.

Source: Ishikawa T. et al. Atorvastatin exhibits anticancer effects by inhibiting YAP/TAZ activity in mesenchymal-like non-small cell lung cancer. Scientific Reports 15:30167 (published 18 August 2025). https://doi.org/10.1038/s41598-025-15624-2