Statins May Halt Cancer Development By Blocking Inflammatory Pathway

Statin therapy may block an inflammatory protein pathway associated with the development of cancer resulting from chronic inflammation, according to a new study published in Nature Communications.¹

The study identified the Toll-like receptor (TLR)3/4-TBK1-IRF3 signaling axis as a critical regulator of interleukin-33 (IL-33) expression, which can signal inflammation in the skin and pancreas, and contribute to cancer development. Treatment with pitavastatin, a lipophilic statin, suppressed IL-33 expression by blocking the TBK1-IRF3-33 axis, and across a large, human population study, reduced the risk of chronic pancreatitis and pancreatic cancer.

“Chronic inflammation is a major cause of cancer worldwide. We investigated the mechanism by which environmental toxins drive the initiation of cancer-prone chronic inflammation in the skin and pancreas,” senior author Shawn Demehri, MD, PhD, a principal investigator at the Center for Cancer Immunology and Cutaneous Biology Research Center of Massachusetts General Hospital, and an associate professor of dermatology at Harvard Medical School, said in a statement.² “Furthermore, we examined safe and effective therapies to block this pathway in order to suppress chronic inflammation and its cancer aftermath.”

Chronic inflammation is a cause of approximately 20% of cancers globally, with the prevalence of cancer-prone diseases, including pancreatitis, inflammatory bowel disease (IBD), and hepatitis, rising in recent decades.³ However, inhibiting effectors of carcinogenesis in chronic inflammation can be challenging, given their redundant function in cancer promotion, and demonstrating severe side effects.

Demehri and colleagues indicated, that to overcome these issues, it is crucial to create safe agents to prevent the development of chronic inflammation and its cancer sequela.¹ IL-33 is a critical initiation of chronic inflammation, promoting the development of a chronic inflammatory environment in stressed and inflamed tissues.

For the human-focused analysis, human samples, including de-identified formalin-fixed paraffin-embedded human pancreas tissue sections, were obtained from the department of pathology at Massachusetts General Hospital.

Investigators examined IL-33 and IRF3 expression in the epithelial cells across 15 matched samples of a normal pancreas, pancreatitis, and pancreatitis-associated pancreatic ductal adenocarcinoma (PDAC). The analysis revealed that IL-33 and IRF3 were highly expressed in the nucleus of epithelial cells in pancreatitis and PDAC samples.

In addition, the number of IL-33 epithelial cells was positively linked with the amount of IRF3 across the available samples. Demehri and colleagues noted the expression of IL33 and other IRF3 target genes, TNF, IL1B, and CXCL10, were highly upregulated in pancreatic cancer, compared with normal pancreas, in a collection of samples from two large healthcare databases.

The TriNetX Diamond Network database was used to identify the cohort of patients who had received pitavastatin. An FDA-approved drug library screen noted pitavastatin effectively suppresses IL-33 expression by blocking TBK1 membrane recruitment/activation through the mevalonate pathway inhibition.

Using International Classification of Diseases (ICD) codes, patients with a history of chronic pancreatitis and pancreatic cancer before statin initiation were excluded from the cohort. The index date for all analyses comprised the initiation of pitavastatin for study cohorts and ezetimibe, a commonly used cholesterol-lowering agent, for the control cohort.

Upon analysis, the risk of chronic pancreatitis was significantly decreased in the pitavastatin-treated cohort, compared with control patients treated with ezetimibe, which does not affect the mevalonate pathway (odds ratio [OR], 0.81; 95% CI, 0.73 - 0.90; P <.0001). Meanwhile, the risk of pancreatic cancer was notably reduced in the pitavastatin-treated group, compared with the ezetimibe-treated cohort (OR, 0.835; 95% CI, 0.748 - 0.932; P = .0013).

Altogether, based on these findings, Demehri and colleagues suggested the prevention of the TBK1-IRF3-IL-33 signaling axis by statins, which may prevent chronic inflammation and cancer sequelae in patients at high risk.

“Next, we aim to further examine the impact of statins in preventing cancer development in chronic inflammation in liver and gastrointestinal tract, and to identify other novel, therapeutic approaches to suppress cancer-prone chronic inflammation,” Demehri added.

References

1. _{Park, J.H., Mortaja, M., Son, H.G. et al. Statin prevents cancer development in chronic inflammation by blocking interleukin 33 expression. Nat Commun 15, 4099 (2024). https://doi.org/10.1038/s41467-024-48441-8}
2. _{Mass General Brigham Press Release}
3. _{Chen L, Deng H, Cui H, et al. Inflammatory responses and inflammation-associated diseases in organs. Oncotarget. 2017;9(6):7204-7218. Published 2017 Dec 14. doi:10.18632/oncotarget.23208}